User login
Major survey spotlights novel factors influencing acne
MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.
In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented . One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.
“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.
This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.
The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).
The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.
Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.
Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).
Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).
Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .
Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.
“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.
Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.
Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.
Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.
Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.
“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.
However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?
“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”
The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.
In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented . One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.
“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.
This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.
The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).
The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.
Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.
Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).
Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).
Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .
Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.
“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.
Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.
Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.
Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.
Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.
“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.
However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?
“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”
The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.
In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented . One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.
“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.
This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.
The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).
The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.
Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.
Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).
Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).
Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .
Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.
“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.
Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.
Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.
Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.
Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.
“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.
However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?
“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”
The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
REPORTING FROM EADV 2019
No tacrolimus/cancer link in atopic dermatitis in 10-year study
MADRID – participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).
APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.
A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.
The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.
Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.
The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).
The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?
“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”
Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.
MADRID – participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).
APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.
A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.
The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.
Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.
The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).
The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?
“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”
Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.
MADRID – participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).
APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.
A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.
The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.
Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.
The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).
The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?
“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”
Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.
REPORTING FROM THE EADV CONGRESS
Food addiction is pervasive among psychiatric patients
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
REPORTING FROM ECNP 2019
Spotlight is on promising investigational antipsychotics
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
REPORTING FROM ECNP 2019
Remote ischemic conditioning in STEMI, RIP
PARIS – Remote ischemic condition, long viewed as the best hope for the next breakthrough in improved clinical outcomes in acute MI, is now dead as a broad therapeutic strategy as a result of the resoundingly negative results of the CONDI-2/ERIC-PPCI trial, Hans Erik Bøtker, MD, PhD, declared at the annual congress of the European Society of Cardiology.
“I would not be quite honest if I did not admit that we were somewhat disappointed in these results, given the promising results we have seen in the majority of the proof-of-concept studies,” added Dr. Bøtker, professor of cardiovascular medicine and interventional cardiology at Aarhus (Denmark) University.
Remote ischemic conditioning entails imposing brief cycles of ischemia and reperfusion on an arm or leg prior to or during reperfusion of an occluded artery in the setting of acute MI in order to provide cardioprotection against reperfusion injury. In the small proof-of-concept studies, it reduced infarct size and suggested the possibility of better clinical outcomes. But the four-country, prospective, single-blind, randomized CONDI-2/ERIC-PPCI trial, involving 5,401 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI), showed nary a glimmer of the hoped-for clinical benefits from four cycles of 5 minutes of ischemia and 5 minutes of deflation of an automated arm-cuff device.
The primary outcome, a composite of the 12-month rate of cardiac death or heart failure hospitalization, occurred in 9.4% of the remote ischemic conditioning group, which wasn’t significantly different from the 8.6% rate in controls. Nor were there any significant between-group differences in infarct size at 48 hours based upon high-sensitivity troponin T measurement or any of the other prespecified secondary study endpoints.
Discussant Bernard J. Gersh, MB, ChB, PhD, a long-time fervent advocate of remote ischemic conditioning as an important potential advance in MI care, wasn’t an investigator in CONDI-2/ERIC-PPCI, which he characterized as “very well executed, large, and pivotal.”
“The results of this trial are emphatic, and there would appear to be no role for routine remote ischemic conditioning in the management of most – and I would emphasize ‘most,’ perhaps not all, but most – patients with STEMI undergoing primary PCI. The results may not be what we’d hoped to hear, and I share Dr. Bøtker’s disappointment, but the data appear to be conclusive in regard to the majority of the primary PCI population. It is what it is. The only remaining questions are why the result were almost completely universally neutral in CONDI-2/ERIC-PPCI after so many positive experimental models and proof-of-concept studies, and whether are there other patient subsets who might benefit,” according to Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
Pointing to the 30-day cardiac death rate of about 2% in the trial, he commented that the management of STEMI has gotten so good that it becomes very difficult to demonstrate a difference with remote ischemic conditioning, even if a small benefit is actually present.
“I think that’s the era that we now live in,” Dr. Gersh said.
However, he is not ready to throw the final shovelful of dirt on the grave of remote ischemic conditioning.
“There is a group where perhaps there may be a therapeutic benefit: STEMI patients presenting with cardiogenic shock and no cardiac arrest,” he said.
He was a coauthor of a study analyzing the impact of an American Heart Association quality improvement project involving nearly 24,000 STEMI patients. Those with cardiogenic shock but no cardiac arrest had a 23.4% in-hospital mortality (JACC Cardiovasc Interv. 2018 Sep 24;11[18]:1824-33).
“We know that cardiogenic shock is an evolving process, and with this 23% mortality, perhaps myocardial salvage may still make a difference,” Dr. Gersh said.
The full results of CONDI-2/ERIC-PPCI have been published in the Lancet (2019 Oct 19;394[10207]:1415-24). In an accompanying editorial entitled “The Broken Promise of Remote Ischemic Conditioning,” Andrew Peter Vanezis, MD, of Royal Alexandra Hospital in Edmonton, Alta., said that “the role of remote ischemic conditioning in improving the lives of patients with STEMI has been thrown sharply into question. ... It might be time to abandon this form of cardioprotection in favor of more effective therapies” (Lancet. 2019 Oct 19;394:1389-90).
The CONDI-2/ERIC-PPCI study was funded by the British Heart Foundation, University College London, the Danish Innovation Foundation, the Novo Nordisk Foundation, and TrygFonden. Dr. Bøtker reported a financial relationship with CellAegis.
PARIS – Remote ischemic condition, long viewed as the best hope for the next breakthrough in improved clinical outcomes in acute MI, is now dead as a broad therapeutic strategy as a result of the resoundingly negative results of the CONDI-2/ERIC-PPCI trial, Hans Erik Bøtker, MD, PhD, declared at the annual congress of the European Society of Cardiology.
“I would not be quite honest if I did not admit that we were somewhat disappointed in these results, given the promising results we have seen in the majority of the proof-of-concept studies,” added Dr. Bøtker, professor of cardiovascular medicine and interventional cardiology at Aarhus (Denmark) University.
Remote ischemic conditioning entails imposing brief cycles of ischemia and reperfusion on an arm or leg prior to or during reperfusion of an occluded artery in the setting of acute MI in order to provide cardioprotection against reperfusion injury. In the small proof-of-concept studies, it reduced infarct size and suggested the possibility of better clinical outcomes. But the four-country, prospective, single-blind, randomized CONDI-2/ERIC-PPCI trial, involving 5,401 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI), showed nary a glimmer of the hoped-for clinical benefits from four cycles of 5 minutes of ischemia and 5 minutes of deflation of an automated arm-cuff device.
The primary outcome, a composite of the 12-month rate of cardiac death or heart failure hospitalization, occurred in 9.4% of the remote ischemic conditioning group, which wasn’t significantly different from the 8.6% rate in controls. Nor were there any significant between-group differences in infarct size at 48 hours based upon high-sensitivity troponin T measurement or any of the other prespecified secondary study endpoints.
Discussant Bernard J. Gersh, MB, ChB, PhD, a long-time fervent advocate of remote ischemic conditioning as an important potential advance in MI care, wasn’t an investigator in CONDI-2/ERIC-PPCI, which he characterized as “very well executed, large, and pivotal.”
“The results of this trial are emphatic, and there would appear to be no role for routine remote ischemic conditioning in the management of most – and I would emphasize ‘most,’ perhaps not all, but most – patients with STEMI undergoing primary PCI. The results may not be what we’d hoped to hear, and I share Dr. Bøtker’s disappointment, but the data appear to be conclusive in regard to the majority of the primary PCI population. It is what it is. The only remaining questions are why the result were almost completely universally neutral in CONDI-2/ERIC-PPCI after so many positive experimental models and proof-of-concept studies, and whether are there other patient subsets who might benefit,” according to Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
Pointing to the 30-day cardiac death rate of about 2% in the trial, he commented that the management of STEMI has gotten so good that it becomes very difficult to demonstrate a difference with remote ischemic conditioning, even if a small benefit is actually present.
“I think that’s the era that we now live in,” Dr. Gersh said.
However, he is not ready to throw the final shovelful of dirt on the grave of remote ischemic conditioning.
“There is a group where perhaps there may be a therapeutic benefit: STEMI patients presenting with cardiogenic shock and no cardiac arrest,” he said.
He was a coauthor of a study analyzing the impact of an American Heart Association quality improvement project involving nearly 24,000 STEMI patients. Those with cardiogenic shock but no cardiac arrest had a 23.4% in-hospital mortality (JACC Cardiovasc Interv. 2018 Sep 24;11[18]:1824-33).
“We know that cardiogenic shock is an evolving process, and with this 23% mortality, perhaps myocardial salvage may still make a difference,” Dr. Gersh said.
The full results of CONDI-2/ERIC-PPCI have been published in the Lancet (2019 Oct 19;394[10207]:1415-24). In an accompanying editorial entitled “The Broken Promise of Remote Ischemic Conditioning,” Andrew Peter Vanezis, MD, of Royal Alexandra Hospital in Edmonton, Alta., said that “the role of remote ischemic conditioning in improving the lives of patients with STEMI has been thrown sharply into question. ... It might be time to abandon this form of cardioprotection in favor of more effective therapies” (Lancet. 2019 Oct 19;394:1389-90).
The CONDI-2/ERIC-PPCI study was funded by the British Heart Foundation, University College London, the Danish Innovation Foundation, the Novo Nordisk Foundation, and TrygFonden. Dr. Bøtker reported a financial relationship with CellAegis.
PARIS – Remote ischemic condition, long viewed as the best hope for the next breakthrough in improved clinical outcomes in acute MI, is now dead as a broad therapeutic strategy as a result of the resoundingly negative results of the CONDI-2/ERIC-PPCI trial, Hans Erik Bøtker, MD, PhD, declared at the annual congress of the European Society of Cardiology.
“I would not be quite honest if I did not admit that we were somewhat disappointed in these results, given the promising results we have seen in the majority of the proof-of-concept studies,” added Dr. Bøtker, professor of cardiovascular medicine and interventional cardiology at Aarhus (Denmark) University.
Remote ischemic conditioning entails imposing brief cycles of ischemia and reperfusion on an arm or leg prior to or during reperfusion of an occluded artery in the setting of acute MI in order to provide cardioprotection against reperfusion injury. In the small proof-of-concept studies, it reduced infarct size and suggested the possibility of better clinical outcomes. But the four-country, prospective, single-blind, randomized CONDI-2/ERIC-PPCI trial, involving 5,401 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI), showed nary a glimmer of the hoped-for clinical benefits from four cycles of 5 minutes of ischemia and 5 minutes of deflation of an automated arm-cuff device.
The primary outcome, a composite of the 12-month rate of cardiac death or heart failure hospitalization, occurred in 9.4% of the remote ischemic conditioning group, which wasn’t significantly different from the 8.6% rate in controls. Nor were there any significant between-group differences in infarct size at 48 hours based upon high-sensitivity troponin T measurement or any of the other prespecified secondary study endpoints.
Discussant Bernard J. Gersh, MB, ChB, PhD, a long-time fervent advocate of remote ischemic conditioning as an important potential advance in MI care, wasn’t an investigator in CONDI-2/ERIC-PPCI, which he characterized as “very well executed, large, and pivotal.”
“The results of this trial are emphatic, and there would appear to be no role for routine remote ischemic conditioning in the management of most – and I would emphasize ‘most,’ perhaps not all, but most – patients with STEMI undergoing primary PCI. The results may not be what we’d hoped to hear, and I share Dr. Bøtker’s disappointment, but the data appear to be conclusive in regard to the majority of the primary PCI population. It is what it is. The only remaining questions are why the result were almost completely universally neutral in CONDI-2/ERIC-PPCI after so many positive experimental models and proof-of-concept studies, and whether are there other patient subsets who might benefit,” according to Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
Pointing to the 30-day cardiac death rate of about 2% in the trial, he commented that the management of STEMI has gotten so good that it becomes very difficult to demonstrate a difference with remote ischemic conditioning, even if a small benefit is actually present.
“I think that’s the era that we now live in,” Dr. Gersh said.
However, he is not ready to throw the final shovelful of dirt on the grave of remote ischemic conditioning.
“There is a group where perhaps there may be a therapeutic benefit: STEMI patients presenting with cardiogenic shock and no cardiac arrest,” he said.
He was a coauthor of a study analyzing the impact of an American Heart Association quality improvement project involving nearly 24,000 STEMI patients. Those with cardiogenic shock but no cardiac arrest had a 23.4% in-hospital mortality (JACC Cardiovasc Interv. 2018 Sep 24;11[18]:1824-33).
“We know that cardiogenic shock is an evolving process, and with this 23% mortality, perhaps myocardial salvage may still make a difference,” Dr. Gersh said.
The full results of CONDI-2/ERIC-PPCI have been published in the Lancet (2019 Oct 19;394[10207]:1415-24). In an accompanying editorial entitled “The Broken Promise of Remote Ischemic Conditioning,” Andrew Peter Vanezis, MD, of Royal Alexandra Hospital in Edmonton, Alta., said that “the role of remote ischemic conditioning in improving the lives of patients with STEMI has been thrown sharply into question. ... It might be time to abandon this form of cardioprotection in favor of more effective therapies” (Lancet. 2019 Oct 19;394:1389-90).
The CONDI-2/ERIC-PPCI study was funded by the British Heart Foundation, University College London, the Danish Innovation Foundation, the Novo Nordisk Foundation, and TrygFonden. Dr. Bøtker reported a financial relationship with CellAegis.
REPORTING FROM THE ESC CONGRESS 2019
Certain diabetes drugs may thwart dementia
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
REPORTING FROM ECNP 2019
Once-daily oral JAK inhibitor for atopic dermatitis effective in phase 3 study
MADRID – (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.
“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.
JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.
The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.
A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.
Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.
Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.
“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.
Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.
Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.
“We need long-term safety data, of course,” he said.
Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.
Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”
Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.
Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).
Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.
MADRID – (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.
“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.
JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.
The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.
A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.
Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.
Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.
“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.
Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.
Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.
“We need long-term safety data, of course,” he said.
Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.
Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”
Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.
Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).
Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.
MADRID – (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.
“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland.
JADE MONO-1 (JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.
The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.
A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.
Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.
Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.
“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.
Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.
Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.
“We need long-term safety data, of course,” he said.
Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.
Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”
Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.
Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published (JAMA Dermatol. 2019 Oct 2. doi: 10.1001/jamadermatol.2019.2855).
Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.
REPORTING FROM THE EADV CONGRESS
Rituximab bests mycophenolate in pemphigus vulgaris
MADRID – Pascal Joly, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Not only did rituximab prove superior in terms of efficacy in the PEMPHIX trial, with a five times greater likelihood of achieving a complete remission lasting for at least 16 weeks while off oral corticosteroids than with mycophenolate mofetil in the 52-week study, but the total number of disease flares in the mycophenolate mofetil group was five times higher. Moreover, rituximab-treated patients received a markedly lower cumulative dose of prednisone as well.
“Rituximab has a superior overall benefit-risk profile, compared to mycophenolate mofetil, in patients with moderate to severe pemphigus vulgaris,” concluded Dr. Joly, professor of dermatology at the University of Rouen (France) and president of the French Society of Dermatology.
The study was undertaken because mycophenolate mofetil is commonly used as a corticosteroid-sparing drug in patients with pemphigus vulgaris, even though its efficacy for the treatment of this rare, severe autoimmune blistering disease is unproven, he explained.
In contrast, rituximab was approved by the Food and Drug Administration and European regulators for treatment of pemphigus vulgaris on the strength of the pivotal phase 3 Ritux 3 trial – also led by Dr. Joly – which demonstrated the superiority of this intravenously administered anti-CD20 monoclonal antibody plus short-term prednisone over high-dose corticosteroid monotherapy, which for decades had been the standard treatment despite its considerable toxicity burden (Lancet. 2017 May 20;389[10083]:2031-40).
An independently conducted analysis of Ritux 3 recently concluded that rituximab plus short-term prednisone was more effective than prednisone alone, with a lower risk of life-threatening, corticosteroid-related adverse events and less cumulative corticosteroid exposure (Br J Dermatol. 2019 Sep 5. doi: 10.1111/bjd.18482).
Also, an international panel of 93 pemphigus experts has declared that rituximab should be considered an evidence-based first-line therapy for moderate to-severe pemphigus (J Am Acad Dermatol. 2018 Feb 10. doi: 10.1016/j.jaad.2018.02.021).
The phase 3, placebo-controlled PEMPHIX trial randomized 135 patients with moderate or severe pemphigus at 49 academic medical centers in the United States and nine other countries to double-blind rituximab or mycophenolate mofetil on top of background oral prednisone at 1.0-1.5 mg/kg per day, with the steroid to be tapered and discontinued within 4-6 months.
The primary endpoint of the study was the proportion of patients in each study arm at week 52 who had achieved a sustained complete remission lasting for at least 16 weeks while off prednisone. The rate was 40.3% in the rituximab group and 9.5% with mycophenolate mofetil, for a 383% increased likelihood of sustained complete remission in the rituximab group.
In addition, all of the study’s secondary endpoints significantly favored rituximab. The median cumulative dose of corticosteroid was 2.7 g through 52 weeks in the rituximab arm, compared with 4 g with mycophenolate mofetil. The total number of disease flares over 52 weeks was 6 in the rituximab group and 44 in the mycophenolate arm. Five rituximab-treated patients experienced disease flares, as did 26 on mycophenolate. Thus, the likelihood of a flare was seven times lower with rituximab.
Scores on the Dermatology Life Quality Index improved by an average of 8.87 points from baseline to week 52 in the rituximab group versus 6 points with mycophenolate. And 62.7% of rituximab-treated patients had a week-52 Dermatology Life Quality Index score of 0, meaning no impact of the disease on their quality of life, compared with 25% of the mycophenolate group.
Dr. Joly characterized the safety profile of rituximab as “manageable, with acceptable tolerability.” About 9% of the rituximab group and 7.4% of mycophenolate-treated patients had one or more treatment-related adverse events, a nonsignificant difference. The rate of treatment-related serious infections was 3.0% with rituximab and 2.9% with mycophenolate. Serious infusion reactions leading to study withdrawal occurred in three patients on rituximab and one on mycophenolate. The rate of grade 3 or worse corticosteroid-related adverse events was 1.5% with rituximab and significantly greater at 7.4% with mycophenolate.
An additional 48-week safety assessment beyond the 52-week primary outcome is ongoing.
Asked what future role he sees for mycophenolate in pemphigus vulgaris, Dr. Joly replied that the only study in the literature that shows the drug outperforms placebo was seriously flawed. “In the future, it’s very likely that the indications for use of mycophenolate in pemphigus vulgaris will be fewer and fewer,” the dermatologist added.
In reply to a question about the merits of routine antibiotic prophylaxis against pneumocystis carinii pneumonia in patients taking rituximab for pemphigus vulgaris, Dr. Joly said the incidence isn’t sufficiently high to justify such practice. After all, he noted, there were no cases of pneumocystis carinii pneumonia in rituximab-treated patients in PEMPHIX and only one in Ritux 3.
EADV Scientific Programming Committee Chair Brigitte Dreno, MD, PhD, professor and head of dermatology at University Hospital in Nantes, France, inquired as to whether there’s a role for maintenance therapy in a potent rituximab-based treatment strategy such as utilized in PEMPHIX.
Definitely, Dr. Joly replied. However, further study is required to work out the best maintenance program.
“There are many arguments for maintenance therapy in these patients. For one, the frequency of relapses increases with the length of follow-up. Also, anti–desmoglein-specific T cells can still be detected after rituximab therapy, even in patients in complete remission. So there is a need for maintenance therapy, perhaps at months 6, 12, and 18, but the optimal regimen isn’t determined yet,” according to Dr. Joly.
PEMPHIX was sponsored by F. Hoffmann-La Roche. Dr. Joly reported serving as a consultant to Roche, Amgen, Principia Biopharma, and Argenx.
MADRID – Pascal Joly, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Not only did rituximab prove superior in terms of efficacy in the PEMPHIX trial, with a five times greater likelihood of achieving a complete remission lasting for at least 16 weeks while off oral corticosteroids than with mycophenolate mofetil in the 52-week study, but the total number of disease flares in the mycophenolate mofetil group was five times higher. Moreover, rituximab-treated patients received a markedly lower cumulative dose of prednisone as well.
“Rituximab has a superior overall benefit-risk profile, compared to mycophenolate mofetil, in patients with moderate to severe pemphigus vulgaris,” concluded Dr. Joly, professor of dermatology at the University of Rouen (France) and president of the French Society of Dermatology.
The study was undertaken because mycophenolate mofetil is commonly used as a corticosteroid-sparing drug in patients with pemphigus vulgaris, even though its efficacy for the treatment of this rare, severe autoimmune blistering disease is unproven, he explained.
In contrast, rituximab was approved by the Food and Drug Administration and European regulators for treatment of pemphigus vulgaris on the strength of the pivotal phase 3 Ritux 3 trial – also led by Dr. Joly – which demonstrated the superiority of this intravenously administered anti-CD20 monoclonal antibody plus short-term prednisone over high-dose corticosteroid monotherapy, which for decades had been the standard treatment despite its considerable toxicity burden (Lancet. 2017 May 20;389[10083]:2031-40).
An independently conducted analysis of Ritux 3 recently concluded that rituximab plus short-term prednisone was more effective than prednisone alone, with a lower risk of life-threatening, corticosteroid-related adverse events and less cumulative corticosteroid exposure (Br J Dermatol. 2019 Sep 5. doi: 10.1111/bjd.18482).
Also, an international panel of 93 pemphigus experts has declared that rituximab should be considered an evidence-based first-line therapy for moderate to-severe pemphigus (J Am Acad Dermatol. 2018 Feb 10. doi: 10.1016/j.jaad.2018.02.021).
The phase 3, placebo-controlled PEMPHIX trial randomized 135 patients with moderate or severe pemphigus at 49 academic medical centers in the United States and nine other countries to double-blind rituximab or mycophenolate mofetil on top of background oral prednisone at 1.0-1.5 mg/kg per day, with the steroid to be tapered and discontinued within 4-6 months.
The primary endpoint of the study was the proportion of patients in each study arm at week 52 who had achieved a sustained complete remission lasting for at least 16 weeks while off prednisone. The rate was 40.3% in the rituximab group and 9.5% with mycophenolate mofetil, for a 383% increased likelihood of sustained complete remission in the rituximab group.
In addition, all of the study’s secondary endpoints significantly favored rituximab. The median cumulative dose of corticosteroid was 2.7 g through 52 weeks in the rituximab arm, compared with 4 g with mycophenolate mofetil. The total number of disease flares over 52 weeks was 6 in the rituximab group and 44 in the mycophenolate arm. Five rituximab-treated patients experienced disease flares, as did 26 on mycophenolate. Thus, the likelihood of a flare was seven times lower with rituximab.
Scores on the Dermatology Life Quality Index improved by an average of 8.87 points from baseline to week 52 in the rituximab group versus 6 points with mycophenolate. And 62.7% of rituximab-treated patients had a week-52 Dermatology Life Quality Index score of 0, meaning no impact of the disease on their quality of life, compared with 25% of the mycophenolate group.
Dr. Joly characterized the safety profile of rituximab as “manageable, with acceptable tolerability.” About 9% of the rituximab group and 7.4% of mycophenolate-treated patients had one or more treatment-related adverse events, a nonsignificant difference. The rate of treatment-related serious infections was 3.0% with rituximab and 2.9% with mycophenolate. Serious infusion reactions leading to study withdrawal occurred in three patients on rituximab and one on mycophenolate. The rate of grade 3 or worse corticosteroid-related adverse events was 1.5% with rituximab and significantly greater at 7.4% with mycophenolate.
An additional 48-week safety assessment beyond the 52-week primary outcome is ongoing.
Asked what future role he sees for mycophenolate in pemphigus vulgaris, Dr. Joly replied that the only study in the literature that shows the drug outperforms placebo was seriously flawed. “In the future, it’s very likely that the indications for use of mycophenolate in pemphigus vulgaris will be fewer and fewer,” the dermatologist added.
In reply to a question about the merits of routine antibiotic prophylaxis against pneumocystis carinii pneumonia in patients taking rituximab for pemphigus vulgaris, Dr. Joly said the incidence isn’t sufficiently high to justify such practice. After all, he noted, there were no cases of pneumocystis carinii pneumonia in rituximab-treated patients in PEMPHIX and only one in Ritux 3.
EADV Scientific Programming Committee Chair Brigitte Dreno, MD, PhD, professor and head of dermatology at University Hospital in Nantes, France, inquired as to whether there’s a role for maintenance therapy in a potent rituximab-based treatment strategy such as utilized in PEMPHIX.
Definitely, Dr. Joly replied. However, further study is required to work out the best maintenance program.
“There are many arguments for maintenance therapy in these patients. For one, the frequency of relapses increases with the length of follow-up. Also, anti–desmoglein-specific T cells can still be detected after rituximab therapy, even in patients in complete remission. So there is a need for maintenance therapy, perhaps at months 6, 12, and 18, but the optimal regimen isn’t determined yet,” according to Dr. Joly.
PEMPHIX was sponsored by F. Hoffmann-La Roche. Dr. Joly reported serving as a consultant to Roche, Amgen, Principia Biopharma, and Argenx.
MADRID – Pascal Joly, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Not only did rituximab prove superior in terms of efficacy in the PEMPHIX trial, with a five times greater likelihood of achieving a complete remission lasting for at least 16 weeks while off oral corticosteroids than with mycophenolate mofetil in the 52-week study, but the total number of disease flares in the mycophenolate mofetil group was five times higher. Moreover, rituximab-treated patients received a markedly lower cumulative dose of prednisone as well.
“Rituximab has a superior overall benefit-risk profile, compared to mycophenolate mofetil, in patients with moderate to severe pemphigus vulgaris,” concluded Dr. Joly, professor of dermatology at the University of Rouen (France) and president of the French Society of Dermatology.
The study was undertaken because mycophenolate mofetil is commonly used as a corticosteroid-sparing drug in patients with pemphigus vulgaris, even though its efficacy for the treatment of this rare, severe autoimmune blistering disease is unproven, he explained.
In contrast, rituximab was approved by the Food and Drug Administration and European regulators for treatment of pemphigus vulgaris on the strength of the pivotal phase 3 Ritux 3 trial – also led by Dr. Joly – which demonstrated the superiority of this intravenously administered anti-CD20 monoclonal antibody plus short-term prednisone over high-dose corticosteroid monotherapy, which for decades had been the standard treatment despite its considerable toxicity burden (Lancet. 2017 May 20;389[10083]:2031-40).
An independently conducted analysis of Ritux 3 recently concluded that rituximab plus short-term prednisone was more effective than prednisone alone, with a lower risk of life-threatening, corticosteroid-related adverse events and less cumulative corticosteroid exposure (Br J Dermatol. 2019 Sep 5. doi: 10.1111/bjd.18482).
Also, an international panel of 93 pemphigus experts has declared that rituximab should be considered an evidence-based first-line therapy for moderate to-severe pemphigus (J Am Acad Dermatol. 2018 Feb 10. doi: 10.1016/j.jaad.2018.02.021).
The phase 3, placebo-controlled PEMPHIX trial randomized 135 patients with moderate or severe pemphigus at 49 academic medical centers in the United States and nine other countries to double-blind rituximab or mycophenolate mofetil on top of background oral prednisone at 1.0-1.5 mg/kg per day, with the steroid to be tapered and discontinued within 4-6 months.
The primary endpoint of the study was the proportion of patients in each study arm at week 52 who had achieved a sustained complete remission lasting for at least 16 weeks while off prednisone. The rate was 40.3% in the rituximab group and 9.5% with mycophenolate mofetil, for a 383% increased likelihood of sustained complete remission in the rituximab group.
In addition, all of the study’s secondary endpoints significantly favored rituximab. The median cumulative dose of corticosteroid was 2.7 g through 52 weeks in the rituximab arm, compared with 4 g with mycophenolate mofetil. The total number of disease flares over 52 weeks was 6 in the rituximab group and 44 in the mycophenolate arm. Five rituximab-treated patients experienced disease flares, as did 26 on mycophenolate. Thus, the likelihood of a flare was seven times lower with rituximab.
Scores on the Dermatology Life Quality Index improved by an average of 8.87 points from baseline to week 52 in the rituximab group versus 6 points with mycophenolate. And 62.7% of rituximab-treated patients had a week-52 Dermatology Life Quality Index score of 0, meaning no impact of the disease on their quality of life, compared with 25% of the mycophenolate group.
Dr. Joly characterized the safety profile of rituximab as “manageable, with acceptable tolerability.” About 9% of the rituximab group and 7.4% of mycophenolate-treated patients had one or more treatment-related adverse events, a nonsignificant difference. The rate of treatment-related serious infections was 3.0% with rituximab and 2.9% with mycophenolate. Serious infusion reactions leading to study withdrawal occurred in three patients on rituximab and one on mycophenolate. The rate of grade 3 or worse corticosteroid-related adverse events was 1.5% with rituximab and significantly greater at 7.4% with mycophenolate.
An additional 48-week safety assessment beyond the 52-week primary outcome is ongoing.
Asked what future role he sees for mycophenolate in pemphigus vulgaris, Dr. Joly replied that the only study in the literature that shows the drug outperforms placebo was seriously flawed. “In the future, it’s very likely that the indications for use of mycophenolate in pemphigus vulgaris will be fewer and fewer,” the dermatologist added.
In reply to a question about the merits of routine antibiotic prophylaxis against pneumocystis carinii pneumonia in patients taking rituximab for pemphigus vulgaris, Dr. Joly said the incidence isn’t sufficiently high to justify such practice. After all, he noted, there were no cases of pneumocystis carinii pneumonia in rituximab-treated patients in PEMPHIX and only one in Ritux 3.
EADV Scientific Programming Committee Chair Brigitte Dreno, MD, PhD, professor and head of dermatology at University Hospital in Nantes, France, inquired as to whether there’s a role for maintenance therapy in a potent rituximab-based treatment strategy such as utilized in PEMPHIX.
Definitely, Dr. Joly replied. However, further study is required to work out the best maintenance program.
“There are many arguments for maintenance therapy in these patients. For one, the frequency of relapses increases with the length of follow-up. Also, anti–desmoglein-specific T cells can still be detected after rituximab therapy, even in patients in complete remission. So there is a need for maintenance therapy, perhaps at months 6, 12, and 18, but the optimal regimen isn’t determined yet,” according to Dr. Joly.
PEMPHIX was sponsored by F. Hoffmann-La Roche. Dr. Joly reported serving as a consultant to Roche, Amgen, Principia Biopharma, and Argenx.
REPORTING FROM THE EADV CONGRESS
Psoriasis registry data provide evidence that adalimumab reduces mortality
MADRID – Psoriasis patients on adalimumab for up to 10 years in the prospective, observational, international, real-world ESPRIT registry had a sharply reduced likelihood of all-cause mortality, compared with the age- and sex-matched general population in participating countries, Diamant T. Thaci, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“If someone tells you that you as a dermatologist can save patient lives by controlling psoriasis, you may not believe it. But look at this standardized mortality ratio data,” said Dr. Thaci, professor of dermatology and head of the Comprehensive Center for Inflammation Medicine at the University of Luebeck (Germany).
Indeed, the standardized in routine clinical practice, was 58% lower than expected, based upon published mortality rate data for the general population in the United States, Canada, and the 10 participating European countries. A total of 144 deaths were predicted in the matched general population, yet only 60 deaths occurred in adalimumab-treated registry participants.
This finding is all the more remarkable because ESPRIT participants had high rates of cardiovascular risk factors, as well as a substantial burden of comorbid conditions, as is typical for patients with chronic moderate to severe psoriasis encountered in real-world clinical practice. It’s a different population than enrollees in the long-term, open-label extensions of phase 3, double-blind, randomized, controlled clinical trials of biologics in psoriasis, which at the outset typically excluded patients with baseline substantial comorbidities, he noted.
Moreover, the incidence rates of serious infections, malignancies, and cardiovascular events in ESPRIT participants remained stable over time and well within the range of published rates in psoriasis patients not on biologic therapy.
“All of this underscores the importance of good control of psoriasis,” Dr. Thaci commented.
The ESPRIT registry began enrolling patients and evaluating them every 6 months in 2008, when the vast majority of dermatologists in clinical practice relied upon Physician Global Assessment (PGA) to evaluate treatment efficacy. For this reason, the PGA, rather than the Psoriasis Area and Severity Index, was the main efficacy measure utilized in the registry. The rate of PGA “clear” or “almost clear” was steady over time at 57% at 1 year, 62.1% at 5 years, and 61.5% at 10 years. It should be noted that this was reported in an “as-observed” analysis, which introduces bias favoring a rosier picture of efficacy since by 10 years slightly under half of patients remained on the tumor necrosis factor inhibitor.
However, the primary focus of this ESPRIT analysis was safety, not efficacy. The rate of serious infections was 1.0 event per 100 person-years on adalimumab, compared with published rates of 0.3-2.1 events/100 person-years in psoriasis patients not on a biologic. Malignancies occurred at a rate of 1.3 events/100 person-years in ESPRIT, compared with published rates of 0.5-2.0/100 person-years in psoriasis patients not on biologic therapy. Acute MI occurred at a rate of 0.1 cases/100 person-years in ESPRIT, stroke at 0.2 events/100 person-years, and heart failure at less than 0.1 event/100 person-years, versus a collective rate of 0.6-1.5 events/100 person-years in the comparator population.
Another view of the data is that, at 10 years, 99.4% of ESPRIT participants had not experienced an acute MI, 95.9% hadn’t had a malignancy, and 96.1% remained free of serious infection while on adalimumab, Dr. Thaci continued.
Injection-site reactions, a significant source of concern when adalimumab first reached the marketplace, occurred at a rate of 0.2 events/100 person-years over the course of 10 years. Oral candidiasis, active tuberculosis, demyelinating disorders, and lupus-like reactions were rare, each occurring at an incidence of less than 0.1 event/100 person-years.
Dr. Thaci’s 10-year update from the ongoing registry follows an earlier report of the 5-year results (J Am Acad Dermatol. 2015 Sep;73[3]:410-9.e6).
The ESPRIT registry is sponsored by AbbVie. Dr. Thaci reported serving as a consultant to and/or receiving research grants from that pharmaceutical company and nearly two dozen others.
MADRID – Psoriasis patients on adalimumab for up to 10 years in the prospective, observational, international, real-world ESPRIT registry had a sharply reduced likelihood of all-cause mortality, compared with the age- and sex-matched general population in participating countries, Diamant T. Thaci, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“If someone tells you that you as a dermatologist can save patient lives by controlling psoriasis, you may not believe it. But look at this standardized mortality ratio data,” said Dr. Thaci, professor of dermatology and head of the Comprehensive Center for Inflammation Medicine at the University of Luebeck (Germany).
Indeed, the standardized in routine clinical practice, was 58% lower than expected, based upon published mortality rate data for the general population in the United States, Canada, and the 10 participating European countries. A total of 144 deaths were predicted in the matched general population, yet only 60 deaths occurred in adalimumab-treated registry participants.
This finding is all the more remarkable because ESPRIT participants had high rates of cardiovascular risk factors, as well as a substantial burden of comorbid conditions, as is typical for patients with chronic moderate to severe psoriasis encountered in real-world clinical practice. It’s a different population than enrollees in the long-term, open-label extensions of phase 3, double-blind, randomized, controlled clinical trials of biologics in psoriasis, which at the outset typically excluded patients with baseline substantial comorbidities, he noted.
Moreover, the incidence rates of serious infections, malignancies, and cardiovascular events in ESPRIT participants remained stable over time and well within the range of published rates in psoriasis patients not on biologic therapy.
“All of this underscores the importance of good control of psoriasis,” Dr. Thaci commented.
The ESPRIT registry began enrolling patients and evaluating them every 6 months in 2008, when the vast majority of dermatologists in clinical practice relied upon Physician Global Assessment (PGA) to evaluate treatment efficacy. For this reason, the PGA, rather than the Psoriasis Area and Severity Index, was the main efficacy measure utilized in the registry. The rate of PGA “clear” or “almost clear” was steady over time at 57% at 1 year, 62.1% at 5 years, and 61.5% at 10 years. It should be noted that this was reported in an “as-observed” analysis, which introduces bias favoring a rosier picture of efficacy since by 10 years slightly under half of patients remained on the tumor necrosis factor inhibitor.
However, the primary focus of this ESPRIT analysis was safety, not efficacy. The rate of serious infections was 1.0 event per 100 person-years on adalimumab, compared with published rates of 0.3-2.1 events/100 person-years in psoriasis patients not on a biologic. Malignancies occurred at a rate of 1.3 events/100 person-years in ESPRIT, compared with published rates of 0.5-2.0/100 person-years in psoriasis patients not on biologic therapy. Acute MI occurred at a rate of 0.1 cases/100 person-years in ESPRIT, stroke at 0.2 events/100 person-years, and heart failure at less than 0.1 event/100 person-years, versus a collective rate of 0.6-1.5 events/100 person-years in the comparator population.
Another view of the data is that, at 10 years, 99.4% of ESPRIT participants had not experienced an acute MI, 95.9% hadn’t had a malignancy, and 96.1% remained free of serious infection while on adalimumab, Dr. Thaci continued.
Injection-site reactions, a significant source of concern when adalimumab first reached the marketplace, occurred at a rate of 0.2 events/100 person-years over the course of 10 years. Oral candidiasis, active tuberculosis, demyelinating disorders, and lupus-like reactions were rare, each occurring at an incidence of less than 0.1 event/100 person-years.
Dr. Thaci’s 10-year update from the ongoing registry follows an earlier report of the 5-year results (J Am Acad Dermatol. 2015 Sep;73[3]:410-9.e6).
The ESPRIT registry is sponsored by AbbVie. Dr. Thaci reported serving as a consultant to and/or receiving research grants from that pharmaceutical company and nearly two dozen others.
MADRID – Psoriasis patients on adalimumab for up to 10 years in the prospective, observational, international, real-world ESPRIT registry had a sharply reduced likelihood of all-cause mortality, compared with the age- and sex-matched general population in participating countries, Diamant T. Thaci, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“If someone tells you that you as a dermatologist can save patient lives by controlling psoriasis, you may not believe it. But look at this standardized mortality ratio data,” said Dr. Thaci, professor of dermatology and head of the Comprehensive Center for Inflammation Medicine at the University of Luebeck (Germany).
Indeed, the standardized in routine clinical practice, was 58% lower than expected, based upon published mortality rate data for the general population in the United States, Canada, and the 10 participating European countries. A total of 144 deaths were predicted in the matched general population, yet only 60 deaths occurred in adalimumab-treated registry participants.
This finding is all the more remarkable because ESPRIT participants had high rates of cardiovascular risk factors, as well as a substantial burden of comorbid conditions, as is typical for patients with chronic moderate to severe psoriasis encountered in real-world clinical practice. It’s a different population than enrollees in the long-term, open-label extensions of phase 3, double-blind, randomized, controlled clinical trials of biologics in psoriasis, which at the outset typically excluded patients with baseline substantial comorbidities, he noted.
Moreover, the incidence rates of serious infections, malignancies, and cardiovascular events in ESPRIT participants remained stable over time and well within the range of published rates in psoriasis patients not on biologic therapy.
“All of this underscores the importance of good control of psoriasis,” Dr. Thaci commented.
The ESPRIT registry began enrolling patients and evaluating them every 6 months in 2008, when the vast majority of dermatologists in clinical practice relied upon Physician Global Assessment (PGA) to evaluate treatment efficacy. For this reason, the PGA, rather than the Psoriasis Area and Severity Index, was the main efficacy measure utilized in the registry. The rate of PGA “clear” or “almost clear” was steady over time at 57% at 1 year, 62.1% at 5 years, and 61.5% at 10 years. It should be noted that this was reported in an “as-observed” analysis, which introduces bias favoring a rosier picture of efficacy since by 10 years slightly under half of patients remained on the tumor necrosis factor inhibitor.
However, the primary focus of this ESPRIT analysis was safety, not efficacy. The rate of serious infections was 1.0 event per 100 person-years on adalimumab, compared with published rates of 0.3-2.1 events/100 person-years in psoriasis patients not on a biologic. Malignancies occurred at a rate of 1.3 events/100 person-years in ESPRIT, compared with published rates of 0.5-2.0/100 person-years in psoriasis patients not on biologic therapy. Acute MI occurred at a rate of 0.1 cases/100 person-years in ESPRIT, stroke at 0.2 events/100 person-years, and heart failure at less than 0.1 event/100 person-years, versus a collective rate of 0.6-1.5 events/100 person-years in the comparator population.
Another view of the data is that, at 10 years, 99.4% of ESPRIT participants had not experienced an acute MI, 95.9% hadn’t had a malignancy, and 96.1% remained free of serious infection while on adalimumab, Dr. Thaci continued.
Injection-site reactions, a significant source of concern when adalimumab first reached the marketplace, occurred at a rate of 0.2 events/100 person-years over the course of 10 years. Oral candidiasis, active tuberculosis, demyelinating disorders, and lupus-like reactions were rare, each occurring at an incidence of less than 0.1 event/100 person-years.
Dr. Thaci’s 10-year update from the ongoing registry follows an earlier report of the 5-year results (J Am Acad Dermatol. 2015 Sep;73[3]:410-9.e6).
The ESPRIT registry is sponsored by AbbVie. Dr. Thaci reported serving as a consultant to and/or receiving research grants from that pharmaceutical company and nearly two dozen others.
REPORTING FROM THE EADV CONGRESS
New themes emerging about antipsychotic maintenance therapy
COPENHAGEN – Recent studies emphasize the long-term merits of extending antipsychotic therapy beyond 1 year for patients in remission after a first psychotic episode, Mark Weiser, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Another emerging theme in the research literature, albeit a somewhat heretical one, is the value of antipsychotic polypharmacy, added Dr. Weiser, professor and chairman of the department of psychiatry at Sackler Faculty of Medicine, Tel Aviv University.
“Polypharmacy might not be so bad,” he declared in a keynote lecture in which he highlighted recent major publications addressing issues involving pharmacotherapy of schizophrenia.
“When we were residents, we were all taught that it’s not good to give two antipsychotics together, that all antipsychotics work only through dopamine D2 [receptor] blockade, hence there’s no point in giving more than one antipsychotic because all you’re doing is increasing side effects. But maybe it’s not as simple as that,” the psychiatrist said.
Exhibit 1: A recent Finnish national registry study of 62,250 patients with schizophrenia featuring up to 20-year follow-up showing that any antipsychotic polypharmacy was associated with a significantly lower risk of rehospitalization, compared with any antipsychotic monotherapy. The combination that stood out as having the lowest rehospitalization risk was clozapine plus aripiprazole, with a 14%-23% lower risk than for clozapine alone, which was the most effective monotherapy (JAMA Psychiatry. 2019 May; 76[5]:499-507).
Dr. Weiser pronounced himself a firm believer in the Finnish experience.
“The reason I think that this is true is that it’s exactly what I find in my own VA data,” he said.
Indeed, he and his coinvestigators are preparing to publish the results of their longitudinal study of 37,368 schizophrenia patients in the U.S. Veterans Affairs system. A key finding was that patients on antipsychotic polypharmacy had a longer time to treatment discontinuation than did those on monotherapy.
“Polypharmacy, at least in real-world study designs, seems to be good,” he noted.
Moreover, even in the world of highly selective randomized clinical trials, polypharmacy appears to fare pretty well as a treatment strategy, Dr. Weiser noted. A recent meta-analysis of six RCTs totaling 341 patients showed that switching patients from two antipsychotics to one was associated with a 2.2-fold increased risk of study discontinuation, although the investigators rated the quality of the trials as low to very low (Schizophr Res. 2019 Jul;209:50-7).
“I’m doing more polypharmacy now because of these data,” Dr. Weiser said. “My understanding of the polypharmacy data is that it’s not just blocking dopamine that’s important for treatment efficacy in schizophrenia.”
Getting a handle on first-episode psychosis
Dr. Weiser was a coinvestigator in the European Commission–funded OPTiMiSE study, in which 446 patients with first-episode schizophrenia or schizophreniform disorder in 14 European countries and Israel received 4 weeks of oral amisulpride. Then, if they were not in symptomatic remission, they were randomized double-blind to 6 weeks more of amisulpride or a switch to olanzapine. Those who weren’t in remission at 10 weeks were then placed on 12 weeks of open-label clozapine.
OPTiMiSE validated the clinical utility of a simple treatment algorithm, as 56% of patients achieved remission using stringent criteria by week 4 on amisulpride, and an additional 7% reached that endpoint by week 10, with the switch to olanzapine offering no added value over continued amisulpride. Switching week-10 nonresponders to clozapine enabled 28% of them to achieve remission (Lancet Psychiatry. 2018 Oct 1;5[10]:797-807).
A key take-home message of the trial, Dr. Weiser said, is that a switch to clozapine is justified after 10 weeks of unsuccessful treatment with a first-line antipsychotic; there’s no need to wait until patients have failed on two consecutive antipsychotics, as guidelines now recommend.
He observed that it can be a lot more challenging to keep patients in remission after a first psychotic episode than it is to get them to respond in the first place. For this reason, he found particularly instructive a recent study by psychiatrists at the University of Hong Kong that shined a light on the understudied long-term adverse consequences of stopping antipsychotic therapy after 1 year in patients successfully treated for a first-episode psychosis. At the 1-year point in this randomized trial, the successfully remitted patients were given maintenance therapy or their antipsychotic therapy was discontinued for 12 months. Ten years later, the investigators reported, the rate of a composite endpoint comprising persistent psychotic symptoms, requirement for clozapine, or completed suicide was 21% in the maintenance therapy group and significantly worse at 39% in those who had stopped treatment at 1 year (Lancet Psychiatry. 2018 May 1;5[5]:432-42).
“It’s probably a good idea to keep patients who are stable on maintenance therapy for longer than a year. A lot of first-episode patients don’t want to hear this. A lot of family members don’t want to hear this. And a lot of patients, of course, decide for themselves and stop treatment, although I tell them they should not.
Asked how low his low-dose long-term maintenance therapy is, he replied: “Negotiate with your patient about the lowest dose he or she is willing to take. In my opinion, 1 mg of risperidone is a lot better than 0 mg of risperidone, although that’s not an opinion supported by data.”
Dr. Weiser reported having no financial conflicts regarding his presentation.
COPENHAGEN – Recent studies emphasize the long-term merits of extending antipsychotic therapy beyond 1 year for patients in remission after a first psychotic episode, Mark Weiser, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Another emerging theme in the research literature, albeit a somewhat heretical one, is the value of antipsychotic polypharmacy, added Dr. Weiser, professor and chairman of the department of psychiatry at Sackler Faculty of Medicine, Tel Aviv University.
“Polypharmacy might not be so bad,” he declared in a keynote lecture in which he highlighted recent major publications addressing issues involving pharmacotherapy of schizophrenia.
“When we were residents, we were all taught that it’s not good to give two antipsychotics together, that all antipsychotics work only through dopamine D2 [receptor] blockade, hence there’s no point in giving more than one antipsychotic because all you’re doing is increasing side effects. But maybe it’s not as simple as that,” the psychiatrist said.
Exhibit 1: A recent Finnish national registry study of 62,250 patients with schizophrenia featuring up to 20-year follow-up showing that any antipsychotic polypharmacy was associated with a significantly lower risk of rehospitalization, compared with any antipsychotic monotherapy. The combination that stood out as having the lowest rehospitalization risk was clozapine plus aripiprazole, with a 14%-23% lower risk than for clozapine alone, which was the most effective monotherapy (JAMA Psychiatry. 2019 May; 76[5]:499-507).
Dr. Weiser pronounced himself a firm believer in the Finnish experience.
“The reason I think that this is true is that it’s exactly what I find in my own VA data,” he said.
Indeed, he and his coinvestigators are preparing to publish the results of their longitudinal study of 37,368 schizophrenia patients in the U.S. Veterans Affairs system. A key finding was that patients on antipsychotic polypharmacy had a longer time to treatment discontinuation than did those on monotherapy.
“Polypharmacy, at least in real-world study designs, seems to be good,” he noted.
Moreover, even in the world of highly selective randomized clinical trials, polypharmacy appears to fare pretty well as a treatment strategy, Dr. Weiser noted. A recent meta-analysis of six RCTs totaling 341 patients showed that switching patients from two antipsychotics to one was associated with a 2.2-fold increased risk of study discontinuation, although the investigators rated the quality of the trials as low to very low (Schizophr Res. 2019 Jul;209:50-7).
“I’m doing more polypharmacy now because of these data,” Dr. Weiser said. “My understanding of the polypharmacy data is that it’s not just blocking dopamine that’s important for treatment efficacy in schizophrenia.”
Getting a handle on first-episode psychosis
Dr. Weiser was a coinvestigator in the European Commission–funded OPTiMiSE study, in which 446 patients with first-episode schizophrenia or schizophreniform disorder in 14 European countries and Israel received 4 weeks of oral amisulpride. Then, if they were not in symptomatic remission, they were randomized double-blind to 6 weeks more of amisulpride or a switch to olanzapine. Those who weren’t in remission at 10 weeks were then placed on 12 weeks of open-label clozapine.
OPTiMiSE validated the clinical utility of a simple treatment algorithm, as 56% of patients achieved remission using stringent criteria by week 4 on amisulpride, and an additional 7% reached that endpoint by week 10, with the switch to olanzapine offering no added value over continued amisulpride. Switching week-10 nonresponders to clozapine enabled 28% of them to achieve remission (Lancet Psychiatry. 2018 Oct 1;5[10]:797-807).
A key take-home message of the trial, Dr. Weiser said, is that a switch to clozapine is justified after 10 weeks of unsuccessful treatment with a first-line antipsychotic; there’s no need to wait until patients have failed on two consecutive antipsychotics, as guidelines now recommend.
He observed that it can be a lot more challenging to keep patients in remission after a first psychotic episode than it is to get them to respond in the first place. For this reason, he found particularly instructive a recent study by psychiatrists at the University of Hong Kong that shined a light on the understudied long-term adverse consequences of stopping antipsychotic therapy after 1 year in patients successfully treated for a first-episode psychosis. At the 1-year point in this randomized trial, the successfully remitted patients were given maintenance therapy or their antipsychotic therapy was discontinued for 12 months. Ten years later, the investigators reported, the rate of a composite endpoint comprising persistent psychotic symptoms, requirement for clozapine, or completed suicide was 21% in the maintenance therapy group and significantly worse at 39% in those who had stopped treatment at 1 year (Lancet Psychiatry. 2018 May 1;5[5]:432-42).
“It’s probably a good idea to keep patients who are stable on maintenance therapy for longer than a year. A lot of first-episode patients don’t want to hear this. A lot of family members don’t want to hear this. And a lot of patients, of course, decide for themselves and stop treatment, although I tell them they should not.
Asked how low his low-dose long-term maintenance therapy is, he replied: “Negotiate with your patient about the lowest dose he or she is willing to take. In my opinion, 1 mg of risperidone is a lot better than 0 mg of risperidone, although that’s not an opinion supported by data.”
Dr. Weiser reported having no financial conflicts regarding his presentation.
COPENHAGEN – Recent studies emphasize the long-term merits of extending antipsychotic therapy beyond 1 year for patients in remission after a first psychotic episode, Mark Weiser, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Another emerging theme in the research literature, albeit a somewhat heretical one, is the value of antipsychotic polypharmacy, added Dr. Weiser, professor and chairman of the department of psychiatry at Sackler Faculty of Medicine, Tel Aviv University.
“Polypharmacy might not be so bad,” he declared in a keynote lecture in which he highlighted recent major publications addressing issues involving pharmacotherapy of schizophrenia.
“When we were residents, we were all taught that it’s not good to give two antipsychotics together, that all antipsychotics work only through dopamine D2 [receptor] blockade, hence there’s no point in giving more than one antipsychotic because all you’re doing is increasing side effects. But maybe it’s not as simple as that,” the psychiatrist said.
Exhibit 1: A recent Finnish national registry study of 62,250 patients with schizophrenia featuring up to 20-year follow-up showing that any antipsychotic polypharmacy was associated with a significantly lower risk of rehospitalization, compared with any antipsychotic monotherapy. The combination that stood out as having the lowest rehospitalization risk was clozapine plus aripiprazole, with a 14%-23% lower risk than for clozapine alone, which was the most effective monotherapy (JAMA Psychiatry. 2019 May; 76[5]:499-507).
Dr. Weiser pronounced himself a firm believer in the Finnish experience.
“The reason I think that this is true is that it’s exactly what I find in my own VA data,” he said.
Indeed, he and his coinvestigators are preparing to publish the results of their longitudinal study of 37,368 schizophrenia patients in the U.S. Veterans Affairs system. A key finding was that patients on antipsychotic polypharmacy had a longer time to treatment discontinuation than did those on monotherapy.
“Polypharmacy, at least in real-world study designs, seems to be good,” he noted.
Moreover, even in the world of highly selective randomized clinical trials, polypharmacy appears to fare pretty well as a treatment strategy, Dr. Weiser noted. A recent meta-analysis of six RCTs totaling 341 patients showed that switching patients from two antipsychotics to one was associated with a 2.2-fold increased risk of study discontinuation, although the investigators rated the quality of the trials as low to very low (Schizophr Res. 2019 Jul;209:50-7).
“I’m doing more polypharmacy now because of these data,” Dr. Weiser said. “My understanding of the polypharmacy data is that it’s not just blocking dopamine that’s important for treatment efficacy in schizophrenia.”
Getting a handle on first-episode psychosis
Dr. Weiser was a coinvestigator in the European Commission–funded OPTiMiSE study, in which 446 patients with first-episode schizophrenia or schizophreniform disorder in 14 European countries and Israel received 4 weeks of oral amisulpride. Then, if they were not in symptomatic remission, they were randomized double-blind to 6 weeks more of amisulpride or a switch to olanzapine. Those who weren’t in remission at 10 weeks were then placed on 12 weeks of open-label clozapine.
OPTiMiSE validated the clinical utility of a simple treatment algorithm, as 56% of patients achieved remission using stringent criteria by week 4 on amisulpride, and an additional 7% reached that endpoint by week 10, with the switch to olanzapine offering no added value over continued amisulpride. Switching week-10 nonresponders to clozapine enabled 28% of them to achieve remission (Lancet Psychiatry. 2018 Oct 1;5[10]:797-807).
A key take-home message of the trial, Dr. Weiser said, is that a switch to clozapine is justified after 10 weeks of unsuccessful treatment with a first-line antipsychotic; there’s no need to wait until patients have failed on two consecutive antipsychotics, as guidelines now recommend.
He observed that it can be a lot more challenging to keep patients in remission after a first psychotic episode than it is to get them to respond in the first place. For this reason, he found particularly instructive a recent study by psychiatrists at the University of Hong Kong that shined a light on the understudied long-term adverse consequences of stopping antipsychotic therapy after 1 year in patients successfully treated for a first-episode psychosis. At the 1-year point in this randomized trial, the successfully remitted patients were given maintenance therapy or their antipsychotic therapy was discontinued for 12 months. Ten years later, the investigators reported, the rate of a composite endpoint comprising persistent psychotic symptoms, requirement for clozapine, or completed suicide was 21% in the maintenance therapy group and significantly worse at 39% in those who had stopped treatment at 1 year (Lancet Psychiatry. 2018 May 1;5[5]:432-42).
“It’s probably a good idea to keep patients who are stable on maintenance therapy for longer than a year. A lot of first-episode patients don’t want to hear this. A lot of family members don’t want to hear this. And a lot of patients, of course, decide for themselves and stop treatment, although I tell them they should not.
Asked how low his low-dose long-term maintenance therapy is, he replied: “Negotiate with your patient about the lowest dose he or she is willing to take. In my opinion, 1 mg of risperidone is a lot better than 0 mg of risperidone, although that’s not an opinion supported by data.”
Dr. Weiser reported having no financial conflicts regarding his presentation.
REPORTING FROM ECNP 2019