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Interleukin-23 inhibition for psoriasis shows ‘wow’ factor
GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.
These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.
Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.
Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
Guselkumab
The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.
PASI 100 rates at 2 years were 49%-55% in the three patient groups. Of the patients in these groups, 54%-59% achieved an Investigator’s Global Assessment (IGA) score of 0. IGA scores of 0 or 1, meaning clear or almost clear skin, were present in 82%-85% of patients at 2 years.
“Dropout rate is an important consideration in long-term studies,” observed Dr. Blauvelt, a dermatologist and president of Oregon Medical Research Center in Portland. “For patients on continuous guselkumab there was a 6% dropout rate in the first year and 6% in the second year, so 88% of patients that started guselkumab were still on guselkumab 2 years later. That’s impressive. In the other two groups, the dropout rate was 2% per year.”
A Dermatology Life Quality Index (DLQI) score of 0 or 1, meaning no disease effects on quality of life, was recorded in 62.5% of the continuous guselkumab group at 48 weeks and 71.1% at 2 years.
“The interesting thing here is that, even though the efficacy numbers are fairly constant between year 1 and year 2, the DLQI goes up and up. Surprising? Maybe not. I think it shows patients are getting happier and happier over time with their disease control,” Dr. Blauvelt continued.
Rates of serious adverse events remained low and stable, with no negative surprises during year 2. The serious infection rate was 1.02 cases/100 patient-years in year 1 and 0.84 cases/100 patient-years in year 2. No cases of tuberculosis, opportunistic infections, or serious hypersensitivity reactions occurred during 2 years of treatment.
Tildrakizumab
Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).
“I think these data are very compelling that the loss of response over time is minimal,” according to the dermatologist. “We’ve also seen that safety over 2 years has no surprises; in fact, it’s remarkably quiet. The rate of severe infections, which is important to look at for any treatment suppressing the immune system, is low and occurs almost independent of dose, which is very hopeful. It’s a promising sign.”
Indeed, the serious infection rate was 0.8 cases/100 patient-years regardless of whether subjects were on tildrakizumab at 100 mg or 200 mg.
Controversy over how to report long-term outcomes
A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.
A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.
The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.
To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.
“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.
Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.
“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.
The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.
GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.
These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.
Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.
Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
Guselkumab
The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.
PASI 100 rates at 2 years were 49%-55% in the three patient groups. Of the patients in these groups, 54%-59% achieved an Investigator’s Global Assessment (IGA) score of 0. IGA scores of 0 or 1, meaning clear or almost clear skin, were present in 82%-85% of patients at 2 years.
“Dropout rate is an important consideration in long-term studies,” observed Dr. Blauvelt, a dermatologist and president of Oregon Medical Research Center in Portland. “For patients on continuous guselkumab there was a 6% dropout rate in the first year and 6% in the second year, so 88% of patients that started guselkumab were still on guselkumab 2 years later. That’s impressive. In the other two groups, the dropout rate was 2% per year.”
A Dermatology Life Quality Index (DLQI) score of 0 or 1, meaning no disease effects on quality of life, was recorded in 62.5% of the continuous guselkumab group at 48 weeks and 71.1% at 2 years.
“The interesting thing here is that, even though the efficacy numbers are fairly constant between year 1 and year 2, the DLQI goes up and up. Surprising? Maybe not. I think it shows patients are getting happier and happier over time with their disease control,” Dr. Blauvelt continued.
Rates of serious adverse events remained low and stable, with no negative surprises during year 2. The serious infection rate was 1.02 cases/100 patient-years in year 1 and 0.84 cases/100 patient-years in year 2. No cases of tuberculosis, opportunistic infections, or serious hypersensitivity reactions occurred during 2 years of treatment.
Tildrakizumab
Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).
“I think these data are very compelling that the loss of response over time is minimal,” according to the dermatologist. “We’ve also seen that safety over 2 years has no surprises; in fact, it’s remarkably quiet. The rate of severe infections, which is important to look at for any treatment suppressing the immune system, is low and occurs almost independent of dose, which is very hopeful. It’s a promising sign.”
Indeed, the serious infection rate was 0.8 cases/100 patient-years regardless of whether subjects were on tildrakizumab at 100 mg or 200 mg.
Controversy over how to report long-term outcomes
A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.
A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.
The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.
To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.
“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.
Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.
“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.
The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.
GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.
These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.
Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.
Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
Guselkumab
The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.
PASI 100 rates at 2 years were 49%-55% in the three patient groups. Of the patients in these groups, 54%-59% achieved an Investigator’s Global Assessment (IGA) score of 0. IGA scores of 0 or 1, meaning clear or almost clear skin, were present in 82%-85% of patients at 2 years.
“Dropout rate is an important consideration in long-term studies,” observed Dr. Blauvelt, a dermatologist and president of Oregon Medical Research Center in Portland. “For patients on continuous guselkumab there was a 6% dropout rate in the first year and 6% in the second year, so 88% of patients that started guselkumab were still on guselkumab 2 years later. That’s impressive. In the other two groups, the dropout rate was 2% per year.”
A Dermatology Life Quality Index (DLQI) score of 0 or 1, meaning no disease effects on quality of life, was recorded in 62.5% of the continuous guselkumab group at 48 weeks and 71.1% at 2 years.
“The interesting thing here is that, even though the efficacy numbers are fairly constant between year 1 and year 2, the DLQI goes up and up. Surprising? Maybe not. I think it shows patients are getting happier and happier over time with their disease control,” Dr. Blauvelt continued.
Rates of serious adverse events remained low and stable, with no negative surprises during year 2. The serious infection rate was 1.02 cases/100 patient-years in year 1 and 0.84 cases/100 patient-years in year 2. No cases of tuberculosis, opportunistic infections, or serious hypersensitivity reactions occurred during 2 years of treatment.
Tildrakizumab
Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).
“I think these data are very compelling that the loss of response over time is minimal,” according to the dermatologist. “We’ve also seen that safety over 2 years has no surprises; in fact, it’s remarkably quiet. The rate of severe infections, which is important to look at for any treatment suppressing the immune system, is low and occurs almost independent of dose, which is very hopeful. It’s a promising sign.”
Indeed, the serious infection rate was 0.8 cases/100 patient-years regardless of whether subjects were on tildrakizumab at 100 mg or 200 mg.
Controversy over how to report long-term outcomes
A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.
A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.
The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.
To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.
“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.
Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.
“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.
The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.
expert analysis from tHE EADV CONGRESS
The year’s Top 10 in addiction medicine
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Novel oral orphan drug tames pemphigus
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Five of 12 pemphigus vulgaris patients achieved control of disease activity within the first 4 weeks on the investigational oral Bruton tyrosine kinase inhibitor PRN1008.
Data source: An interim analysis of the first 12 patients with pemphigus vulgaris in an ongoing multicenter, international open-label, phase 2 clinical trial.
Disclosures: The study presenter reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008 and sponsored the Believe-PV trial.
EXCEL: Quality of life better after PCI than CABG
DENVER – Several key validated measures of health status were significantly more favorable a full year after percutaneous coronary intervention using an everolimus-eluting stent than with coronary artery bypass surgery in patients with unprotected left main CAD in the prespecified quality-of-life analysis of the landmark EXCEL trial.
By 3 years of follow-up, there was no longer a difference between the PCI and CABG groups in terms of the various quality-of-life measures, Suzanne J. Baron, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting. Nor as previously reported was there any significant difference in the primary composite endpoint comprised of all-cause mortality, stroke, or MI.
“My take away from this is that these results provide an ideal opportunity to give patients a choice about which choice they would want: An earlier recovery with angioplasty versus really similar outcomes long-term with either procedure. For me, these EXCEL results make me feel that angioplasty for less complex coronary disease is really probably the preferred option,” said John A. Spertus, MD, director of health outcomes research at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City.
“The faster recovery with PCI, the similar angina relief after 3 years, and also the less depression with PCI, which is an important finding, I think – all this goes in favor of PCI for left main disease,” commented Evald H. Christiansen, MD, a cardiologist at Aarhus (Denmark) University and senior investigator in the NOBLE trial (Lancet. 2016 Dec 3;388[10061]:2743-52), which randomized patients to CABG or a stent that’s no longer marketed.
The previously published clinical outcomes of EXCEL (N Engl J Med. 2016 Dec 8;375[23]:2223-35) were based upon a median 3 years of follow-up. Dr. Baron presented updated outcomes in which all study participants had completed the full 3 years of follow-up. The results were little changed: The primary composite endpoint of all-cause mortality, stroke, or MI occurred in 15.2% of the group treated with the everolimus-eluting Xience stent and was closely similar at 14.7% of the CABG patients, while the 12.5% repeat revascularization rate in the PCI arm was significantly greater than the 7.4% rate with CABG.
But the prespecified EXCEL quality-of-life substudy with assessments at baseline, 1 month, 1 year, and 3 years in 1,788 participants is all new information. Among the highlights: The proportion of patients with clinically significant depression as defined by a Patient Health Questionnaire 8 (PHQ-8) score of 10 or more was 21% at baseline in both groups; 8% in the PCI group, compared with 19% in the CABG arm at 1 month; and 8% in the PCI arm versus 12% with CABG at 12 months of follow-up, with the differences at both time points being significant. By 3 years, the rate was 8%-9% in both groups, reported Dr. Baron of Saint Luke’s Mid America Health Institute and the University of Missouri-Kansas City.
“We now have a new treatment for depression: PCI,” quipped session moderator Gregg W. Stone, MD, professor of medicine at Columbia University in New York, who was lead investigator in EXCEL.
Also, scores on the SF-12 physical summary scale improved sharply from a baseline of 39 points in the PCI group during the first month of follow-up while worsening in the CABG group, such that at 1 month the between-group difference averaged 8.2 points. The gap narrowed over the next 11 months, and by 1 year the CABG patients had caught up.
Scores on the Seattle Angina Questionnaire and the Rose Dyspnea Scale were significantly better in the PCI group than the CABG arm at 1 month, but at 12 and 36 months the two groups were indistinguishable in these domains.
Dr. Spertus, who is credited with inventing both the Seattle Angina Questionnaire and the Kansas City Cardiomyopathy Questionnaire, said that in the context of EXCEL he puts more stock in the SF-12 and PHQ-8 results than the angina and dyspnea measures.
Jonathan Hill, MD, an interventional cardiologist at King’s College London, said the EXCEL quality-of-life substudy provides a valuable picture of the real-life impact of sternotomy.
“We mustn’t underplay that, the months and even up to a year of your life for recovery from the revascularization procedure, compared with days of recovery time with PCI. Patients want the option of PCI if it’s available. This data really vindicates that decision making,” he said.
“I think we minimize the recovery period from CABG. People talk a lot about outcomes at 3 years and 5 years, but look at this prolonged recovery. I think that’s very, very important,” said Dr. Grines, chair of cardiology at Hofstra University, Hempstead, N.Y.
The updated full 3-year data show a trend, albeit not statistically significant, for higher all-cause mortality in the PCI group, by a margin of 8% versus 5.8% with CABG. When asked about it, Dr. Baron said she and her coinvestigators took a closer look and determined that the cardiovascular death rate was virtually identical in the two groups.
“You have to wonder if this was just a random signal regarding the non-cardiovascular-associated deaths,” she added.
The EXCEL trial was supported by Abbott Vascular. Dr. Baron reported serving as a consultant to Edwards Lifesciences and St. Jude Medical.
DENVER – Several key validated measures of health status were significantly more favorable a full year after percutaneous coronary intervention using an everolimus-eluting stent than with coronary artery bypass surgery in patients with unprotected left main CAD in the prespecified quality-of-life analysis of the landmark EXCEL trial.
By 3 years of follow-up, there was no longer a difference between the PCI and CABG groups in terms of the various quality-of-life measures, Suzanne J. Baron, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting. Nor as previously reported was there any significant difference in the primary composite endpoint comprised of all-cause mortality, stroke, or MI.
“My take away from this is that these results provide an ideal opportunity to give patients a choice about which choice they would want: An earlier recovery with angioplasty versus really similar outcomes long-term with either procedure. For me, these EXCEL results make me feel that angioplasty for less complex coronary disease is really probably the preferred option,” said John A. Spertus, MD, director of health outcomes research at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City.
“The faster recovery with PCI, the similar angina relief after 3 years, and also the less depression with PCI, which is an important finding, I think – all this goes in favor of PCI for left main disease,” commented Evald H. Christiansen, MD, a cardiologist at Aarhus (Denmark) University and senior investigator in the NOBLE trial (Lancet. 2016 Dec 3;388[10061]:2743-52), which randomized patients to CABG or a stent that’s no longer marketed.
The previously published clinical outcomes of EXCEL (N Engl J Med. 2016 Dec 8;375[23]:2223-35) were based upon a median 3 years of follow-up. Dr. Baron presented updated outcomes in which all study participants had completed the full 3 years of follow-up. The results were little changed: The primary composite endpoint of all-cause mortality, stroke, or MI occurred in 15.2% of the group treated with the everolimus-eluting Xience stent and was closely similar at 14.7% of the CABG patients, while the 12.5% repeat revascularization rate in the PCI arm was significantly greater than the 7.4% rate with CABG.
But the prespecified EXCEL quality-of-life substudy with assessments at baseline, 1 month, 1 year, and 3 years in 1,788 participants is all new information. Among the highlights: The proportion of patients with clinically significant depression as defined by a Patient Health Questionnaire 8 (PHQ-8) score of 10 or more was 21% at baseline in both groups; 8% in the PCI group, compared with 19% in the CABG arm at 1 month; and 8% in the PCI arm versus 12% with CABG at 12 months of follow-up, with the differences at both time points being significant. By 3 years, the rate was 8%-9% in both groups, reported Dr. Baron of Saint Luke’s Mid America Health Institute and the University of Missouri-Kansas City.
“We now have a new treatment for depression: PCI,” quipped session moderator Gregg W. Stone, MD, professor of medicine at Columbia University in New York, who was lead investigator in EXCEL.
Also, scores on the SF-12 physical summary scale improved sharply from a baseline of 39 points in the PCI group during the first month of follow-up while worsening in the CABG group, such that at 1 month the between-group difference averaged 8.2 points. The gap narrowed over the next 11 months, and by 1 year the CABG patients had caught up.
Scores on the Seattle Angina Questionnaire and the Rose Dyspnea Scale were significantly better in the PCI group than the CABG arm at 1 month, but at 12 and 36 months the two groups were indistinguishable in these domains.
Dr. Spertus, who is credited with inventing both the Seattle Angina Questionnaire and the Kansas City Cardiomyopathy Questionnaire, said that in the context of EXCEL he puts more stock in the SF-12 and PHQ-8 results than the angina and dyspnea measures.
Jonathan Hill, MD, an interventional cardiologist at King’s College London, said the EXCEL quality-of-life substudy provides a valuable picture of the real-life impact of sternotomy.
“We mustn’t underplay that, the months and even up to a year of your life for recovery from the revascularization procedure, compared with days of recovery time with PCI. Patients want the option of PCI if it’s available. This data really vindicates that decision making,” he said.
“I think we minimize the recovery period from CABG. People talk a lot about outcomes at 3 years and 5 years, but look at this prolonged recovery. I think that’s very, very important,” said Dr. Grines, chair of cardiology at Hofstra University, Hempstead, N.Y.
The updated full 3-year data show a trend, albeit not statistically significant, for higher all-cause mortality in the PCI group, by a margin of 8% versus 5.8% with CABG. When asked about it, Dr. Baron said she and her coinvestigators took a closer look and determined that the cardiovascular death rate was virtually identical in the two groups.
“You have to wonder if this was just a random signal regarding the non-cardiovascular-associated deaths,” she added.
The EXCEL trial was supported by Abbott Vascular. Dr. Baron reported serving as a consultant to Edwards Lifesciences and St. Jude Medical.
DENVER – Several key validated measures of health status were significantly more favorable a full year after percutaneous coronary intervention using an everolimus-eluting stent than with coronary artery bypass surgery in patients with unprotected left main CAD in the prespecified quality-of-life analysis of the landmark EXCEL trial.
By 3 years of follow-up, there was no longer a difference between the PCI and CABG groups in terms of the various quality-of-life measures, Suzanne J. Baron, MD, reported at the Transcatheter Cardiovascular Therapeutics annual educational meeting. Nor as previously reported was there any significant difference in the primary composite endpoint comprised of all-cause mortality, stroke, or MI.
“My take away from this is that these results provide an ideal opportunity to give patients a choice about which choice they would want: An earlier recovery with angioplasty versus really similar outcomes long-term with either procedure. For me, these EXCEL results make me feel that angioplasty for less complex coronary disease is really probably the preferred option,” said John A. Spertus, MD, director of health outcomes research at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City.
“The faster recovery with PCI, the similar angina relief after 3 years, and also the less depression with PCI, which is an important finding, I think – all this goes in favor of PCI for left main disease,” commented Evald H. Christiansen, MD, a cardiologist at Aarhus (Denmark) University and senior investigator in the NOBLE trial (Lancet. 2016 Dec 3;388[10061]:2743-52), which randomized patients to CABG or a stent that’s no longer marketed.
The previously published clinical outcomes of EXCEL (N Engl J Med. 2016 Dec 8;375[23]:2223-35) were based upon a median 3 years of follow-up. Dr. Baron presented updated outcomes in which all study participants had completed the full 3 years of follow-up. The results were little changed: The primary composite endpoint of all-cause mortality, stroke, or MI occurred in 15.2% of the group treated with the everolimus-eluting Xience stent and was closely similar at 14.7% of the CABG patients, while the 12.5% repeat revascularization rate in the PCI arm was significantly greater than the 7.4% rate with CABG.
But the prespecified EXCEL quality-of-life substudy with assessments at baseline, 1 month, 1 year, and 3 years in 1,788 participants is all new information. Among the highlights: The proportion of patients with clinically significant depression as defined by a Patient Health Questionnaire 8 (PHQ-8) score of 10 or more was 21% at baseline in both groups; 8% in the PCI group, compared with 19% in the CABG arm at 1 month; and 8% in the PCI arm versus 12% with CABG at 12 months of follow-up, with the differences at both time points being significant. By 3 years, the rate was 8%-9% in both groups, reported Dr. Baron of Saint Luke’s Mid America Health Institute and the University of Missouri-Kansas City.
“We now have a new treatment for depression: PCI,” quipped session moderator Gregg W. Stone, MD, professor of medicine at Columbia University in New York, who was lead investigator in EXCEL.
Also, scores on the SF-12 physical summary scale improved sharply from a baseline of 39 points in the PCI group during the first month of follow-up while worsening in the CABG group, such that at 1 month the between-group difference averaged 8.2 points. The gap narrowed over the next 11 months, and by 1 year the CABG patients had caught up.
Scores on the Seattle Angina Questionnaire and the Rose Dyspnea Scale were significantly better in the PCI group than the CABG arm at 1 month, but at 12 and 36 months the two groups were indistinguishable in these domains.
Dr. Spertus, who is credited with inventing both the Seattle Angina Questionnaire and the Kansas City Cardiomyopathy Questionnaire, said that in the context of EXCEL he puts more stock in the SF-12 and PHQ-8 results than the angina and dyspnea measures.
Jonathan Hill, MD, an interventional cardiologist at King’s College London, said the EXCEL quality-of-life substudy provides a valuable picture of the real-life impact of sternotomy.
“We mustn’t underplay that, the months and even up to a year of your life for recovery from the revascularization procedure, compared with days of recovery time with PCI. Patients want the option of PCI if it’s available. This data really vindicates that decision making,” he said.
“I think we minimize the recovery period from CABG. People talk a lot about outcomes at 3 years and 5 years, but look at this prolonged recovery. I think that’s very, very important,” said Dr. Grines, chair of cardiology at Hofstra University, Hempstead, N.Y.
The updated full 3-year data show a trend, albeit not statistically significant, for higher all-cause mortality in the PCI group, by a margin of 8% versus 5.8% with CABG. When asked about it, Dr. Baron said she and her coinvestigators took a closer look and determined that the cardiovascular death rate was virtually identical in the two groups.
“You have to wonder if this was just a random signal regarding the non-cardiovascular-associated deaths,” she added.
The EXCEL trial was supported by Abbott Vascular. Dr. Baron reported serving as a consultant to Edwards Lifesciences and St. Jude Medical.
AT TCT 2017
Key clinical point:
Major finding: The rate of clinically significant depression 1 year after revascularization of unprotected left main CAD via PCI using an everolimus-eluting stent was 8%, significantly lower than the 12% rate in CABG patients.
Data source: This was a prespecified prospective quality-of-life substudy featuring 3 years of follow-up in 1,788 patients randomized to PCI or CABG.
Disclosures: The EXCEL trial was supported by Abbott Vascular. The presenter reported serving as a consultant to Edwards Lifesciences and St. Jude Medical.
Bare metal stents: Rest in peace
DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.
“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
“This trial adds to what I think is now a very large body of evidence showing that DES [drug-eluting stents] are the way to go, pretty much across the board, putting aside the economic factors that might come into play in certain regions of the world,” Deepak L. Bhatt, MD, commented at the meeting sponsored by the Cardiovascular Research Foundation.
“I think in general there’s really no good reason to use a BMS. I’d use a DES. I think DES is a winning strategy, whether it’s for a thrombotic lesion or an older patient,” added Dr. Bhatt, professor of medicine at Harvard Medical School in Boston and executive director of international cardiovascular programs at Brigham and Women’s Hospital.
Martin B. Leon, MD, concurred.
“I cannot think of any indication for using a BMS anymore, other than cost considerations. I think this study is yet another nail in the coffin of BMS. I think they should be relegated to the past because they really have very little role in environments where DES – which are becoming much more cost-efficient – can be used,” said Dr. Leon, professor of medicine at Columbia University and director of the Center for Interventional Vascular Therapy at New York-Presbyterian/Columbia University Medical Center, New York. Yet in contemporary practice many cardiologists turn to BMS for percutaneous coronary intervention (PCI) in elderly patients with coronary artery disease (CAD), reasoning that the shorter DAPT duration recommended for BMS in the practice guidelines is attractive as a means of minimizing the risk of bleeding complications, which is typically high in the elderly.
The SENIOR trial demonstrates that using a modern DES in combination with the shortened 1- or 6-month DAPT duration typically reserved for BMS recipients results in fewer major adverse cardiac and cerebrovascular events with no increase in bleeding, compared with BMS. This is a finding of high clinical relevance because so many elderly patients undergo PCI; indeed, today one in four PCI patients in the United States is over age 75, explained Dr. Varenne of Cochin Hospital in Paris.
SENIOR was a single-blind, randomized trial of 1,200 PCI patients age 75 and older at 44 centers in nine countries. Their mean age was 81.4 years. This was essentially an all-comers trial: 45% of participants had an acute coronary syndrome, 55% had stable or silent CAD. If they had stable CAD, they were slated for 1 month of DAPT. If they had ACS, they got 6 months of DAPT. All participants were then randomized to PCI with either the thin-strut everolimus-eluting bioabsorbable polymer Synergy DES or the thin-strut Omega or Rebel BMS.
The primary composite efficacy endpoint was the 1-year rate of all-cause mortality, acute MI, stroke, or ischemia-driven target lesion revascularization. The rate was 11.6% in the DES group and 16.4% in the BMS group, for a 29% reduction in favor of the DES strategy and a favorably low number-needed-to-treat of 21. The difference in outcome was driven mainly by a higher ischemia-driven target lesion revascularization rate in the BMS group.
The 1-year rate of bleeding complications was 5% in each group. Probable or definite stent thrombosis occurred in 0.5% of the DES group and 1.4% of the BMS group at 1 year. Ten of the 11 cases of stent thrombosis in the study occurred during the first 30 days after PCI while the patients were on DAPT; the other case occurred on day 31, the day after DAPT was stopped.
Discussant Eric D. Peterson, MD, applauded Dr. Varenne and his coinvestigators for conducting a study focused on elderly individuals, an understudied population largely excluded from the landmark clinical trials in interventional cardiology.
He found the study convincing: “My takeaway is DES is better than BMS. As it is in young people, it continues in old.”
But the study leaves two important questions unanswered: Is the Synergy stent the best DES in the elderly, and what is the best duration of DAPT therapy? Ideally, the SENIOR trial would have included a study arm with the standard 6- and 12-month DAPT durations recommended in the American guidelines for DES recipients with stable and unstable CAD, respectively, observed Dr. Peterson, professor of medicine at Duke University in Durham, N.C., and director of the Duke Clinical Research Institute.
Dr. Varenne replied that SENIOR wasn’t designed as a DAPT duration trial. DAPT duration wasn’t randomized. But other planned and ongoing studies are attempting to define the best DAPT durations in various patient subsets.
Dr. Bhatt said he believes the superiority of contemporary DES over modern BMS is a class effect.
The SENIOR trial was funded by Boston Scientific. Dr. Varenne reported receiving lecture fees from that company as well as Abbott Vascular, AstraZeneca, and Servier within the past year.
DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.
“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
“This trial adds to what I think is now a very large body of evidence showing that DES [drug-eluting stents] are the way to go, pretty much across the board, putting aside the economic factors that might come into play in certain regions of the world,” Deepak L. Bhatt, MD, commented at the meeting sponsored by the Cardiovascular Research Foundation.
“I think in general there’s really no good reason to use a BMS. I’d use a DES. I think DES is a winning strategy, whether it’s for a thrombotic lesion or an older patient,” added Dr. Bhatt, professor of medicine at Harvard Medical School in Boston and executive director of international cardiovascular programs at Brigham and Women’s Hospital.
Martin B. Leon, MD, concurred.
“I cannot think of any indication for using a BMS anymore, other than cost considerations. I think this study is yet another nail in the coffin of BMS. I think they should be relegated to the past because they really have very little role in environments where DES – which are becoming much more cost-efficient – can be used,” said Dr. Leon, professor of medicine at Columbia University and director of the Center for Interventional Vascular Therapy at New York-Presbyterian/Columbia University Medical Center, New York. Yet in contemporary practice many cardiologists turn to BMS for percutaneous coronary intervention (PCI) in elderly patients with coronary artery disease (CAD), reasoning that the shorter DAPT duration recommended for BMS in the practice guidelines is attractive as a means of minimizing the risk of bleeding complications, which is typically high in the elderly.
The SENIOR trial demonstrates that using a modern DES in combination with the shortened 1- or 6-month DAPT duration typically reserved for BMS recipients results in fewer major adverse cardiac and cerebrovascular events with no increase in bleeding, compared with BMS. This is a finding of high clinical relevance because so many elderly patients undergo PCI; indeed, today one in four PCI patients in the United States is over age 75, explained Dr. Varenne of Cochin Hospital in Paris.
SENIOR was a single-blind, randomized trial of 1,200 PCI patients age 75 and older at 44 centers in nine countries. Their mean age was 81.4 years. This was essentially an all-comers trial: 45% of participants had an acute coronary syndrome, 55% had stable or silent CAD. If they had stable CAD, they were slated for 1 month of DAPT. If they had ACS, they got 6 months of DAPT. All participants were then randomized to PCI with either the thin-strut everolimus-eluting bioabsorbable polymer Synergy DES or the thin-strut Omega or Rebel BMS.
The primary composite efficacy endpoint was the 1-year rate of all-cause mortality, acute MI, stroke, or ischemia-driven target lesion revascularization. The rate was 11.6% in the DES group and 16.4% in the BMS group, for a 29% reduction in favor of the DES strategy and a favorably low number-needed-to-treat of 21. The difference in outcome was driven mainly by a higher ischemia-driven target lesion revascularization rate in the BMS group.
The 1-year rate of bleeding complications was 5% in each group. Probable or definite stent thrombosis occurred in 0.5% of the DES group and 1.4% of the BMS group at 1 year. Ten of the 11 cases of stent thrombosis in the study occurred during the first 30 days after PCI while the patients were on DAPT; the other case occurred on day 31, the day after DAPT was stopped.
Discussant Eric D. Peterson, MD, applauded Dr. Varenne and his coinvestigators for conducting a study focused on elderly individuals, an understudied population largely excluded from the landmark clinical trials in interventional cardiology.
He found the study convincing: “My takeaway is DES is better than BMS. As it is in young people, it continues in old.”
But the study leaves two important questions unanswered: Is the Synergy stent the best DES in the elderly, and what is the best duration of DAPT therapy? Ideally, the SENIOR trial would have included a study arm with the standard 6- and 12-month DAPT durations recommended in the American guidelines for DES recipients with stable and unstable CAD, respectively, observed Dr. Peterson, professor of medicine at Duke University in Durham, N.C., and director of the Duke Clinical Research Institute.
Dr. Varenne replied that SENIOR wasn’t designed as a DAPT duration trial. DAPT duration wasn’t randomized. But other planned and ongoing studies are attempting to define the best DAPT durations in various patient subsets.
Dr. Bhatt said he believes the superiority of contemporary DES over modern BMS is a class effect.
The SENIOR trial was funded by Boston Scientific. Dr. Varenne reported receiving lecture fees from that company as well as Abbott Vascular, AstraZeneca, and Servier within the past year.
DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.
“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.
“This trial adds to what I think is now a very large body of evidence showing that DES [drug-eluting stents] are the way to go, pretty much across the board, putting aside the economic factors that might come into play in certain regions of the world,” Deepak L. Bhatt, MD, commented at the meeting sponsored by the Cardiovascular Research Foundation.
“I think in general there’s really no good reason to use a BMS. I’d use a DES. I think DES is a winning strategy, whether it’s for a thrombotic lesion or an older patient,” added Dr. Bhatt, professor of medicine at Harvard Medical School in Boston and executive director of international cardiovascular programs at Brigham and Women’s Hospital.
Martin B. Leon, MD, concurred.
“I cannot think of any indication for using a BMS anymore, other than cost considerations. I think this study is yet another nail in the coffin of BMS. I think they should be relegated to the past because they really have very little role in environments where DES – which are becoming much more cost-efficient – can be used,” said Dr. Leon, professor of medicine at Columbia University and director of the Center for Interventional Vascular Therapy at New York-Presbyterian/Columbia University Medical Center, New York. Yet in contemporary practice many cardiologists turn to BMS for percutaneous coronary intervention (PCI) in elderly patients with coronary artery disease (CAD), reasoning that the shorter DAPT duration recommended for BMS in the practice guidelines is attractive as a means of minimizing the risk of bleeding complications, which is typically high in the elderly.
The SENIOR trial demonstrates that using a modern DES in combination with the shortened 1- or 6-month DAPT duration typically reserved for BMS recipients results in fewer major adverse cardiac and cerebrovascular events with no increase in bleeding, compared with BMS. This is a finding of high clinical relevance because so many elderly patients undergo PCI; indeed, today one in four PCI patients in the United States is over age 75, explained Dr. Varenne of Cochin Hospital in Paris.
SENIOR was a single-blind, randomized trial of 1,200 PCI patients age 75 and older at 44 centers in nine countries. Their mean age was 81.4 years. This was essentially an all-comers trial: 45% of participants had an acute coronary syndrome, 55% had stable or silent CAD. If they had stable CAD, they were slated for 1 month of DAPT. If they had ACS, they got 6 months of DAPT. All participants were then randomized to PCI with either the thin-strut everolimus-eluting bioabsorbable polymer Synergy DES or the thin-strut Omega or Rebel BMS.
The primary composite efficacy endpoint was the 1-year rate of all-cause mortality, acute MI, stroke, or ischemia-driven target lesion revascularization. The rate was 11.6% in the DES group and 16.4% in the BMS group, for a 29% reduction in favor of the DES strategy and a favorably low number-needed-to-treat of 21. The difference in outcome was driven mainly by a higher ischemia-driven target lesion revascularization rate in the BMS group.
The 1-year rate of bleeding complications was 5% in each group. Probable or definite stent thrombosis occurred in 0.5% of the DES group and 1.4% of the BMS group at 1 year. Ten of the 11 cases of stent thrombosis in the study occurred during the first 30 days after PCI while the patients were on DAPT; the other case occurred on day 31, the day after DAPT was stopped.
Discussant Eric D. Peterson, MD, applauded Dr. Varenne and his coinvestigators for conducting a study focused on elderly individuals, an understudied population largely excluded from the landmark clinical trials in interventional cardiology.
He found the study convincing: “My takeaway is DES is better than BMS. As it is in young people, it continues in old.”
But the study leaves two important questions unanswered: Is the Synergy stent the best DES in the elderly, and what is the best duration of DAPT therapy? Ideally, the SENIOR trial would have included a study arm with the standard 6- and 12-month DAPT durations recommended in the American guidelines for DES recipients with stable and unstable CAD, respectively, observed Dr. Peterson, professor of medicine at Duke University in Durham, N.C., and director of the Duke Clinical Research Institute.
Dr. Varenne replied that SENIOR wasn’t designed as a DAPT duration trial. DAPT duration wasn’t randomized. But other planned and ongoing studies are attempting to define the best DAPT durations in various patient subsets.
Dr. Bhatt said he believes the superiority of contemporary DES over modern BMS is a class effect.
The SENIOR trial was funded by Boston Scientific. Dr. Varenne reported receiving lecture fees from that company as well as Abbott Vascular, AstraZeneca, and Servier within the past year.
AT TCT 2017
Key clinical point:
Major finding: The number of elderly patients with CAD who would need to be treated with a contemporary drug-eluting stent backed by a shortened DAPT regimen instead of a modern-era bare metal stent in order to avoid one additional major adverse cardiac and cerebrovascular event over the course of a year is 21.
Data source: This randomized, prospective, single-blind trial included 1,200 patients age 75 or older who underwent PCI at 44 centers in nine countries.
Disclosures: The SENIOR trial was funded by Boston Scientific. The presenter reported receiving lecture fees from that company as well as Abbott Vascular, AstraZeneca, and Servier within the past year.
Early inguinal hernia linked to schizophrenia
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Swedish boys diagnosed with inguinal hernia before age 13 years were 56% more likely to be diagnosed with schizophrenia or schizoaffective disorder later in life.
Data source: This retrospective cohort study included nearly 1.3 million Swedes, 20,705 of whom were diagnosed with an inguinal hernia before age 13 years.
Disclosures: The study was supported by a grant from the Swedish Society of Medicine. The presenter reported having no financial conflicts.
Antidepressant therapy is too often tardy
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Forty percent of U.S. adults diagnosed with major depressive disorder who received an SSRI or an SNRI as initial pharmacotherapy weren’t on the minimum therapeutic dose within 4 weeks of diagnosis.
Data source: A retrospective real-world analysis of claims data on 60,433 U.S. adult outpatients diagnosed with major depressive disorder.
Disclosures: The study was funded by Pfizer and presented by a company employee.
ADHD and insomnia appear intertwined
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Inhaled loxapine quells agitation in personality disorders
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Eleven of 14 acutely agitated patients with various personality disorders were calm, nonsedated, and ready for assessment within 10 minutes after a single dose of inhaled loxapine.
Data source: A prospective observational pilot study of inhaled loxapine in 14 acutely agitated patients with personality disorders.
Disclosures: The study presenter reported having no financial conflicts of interest.
Treatment-resistant depression boosts early mortality
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Young adult Swedes with treatment-resistant major depressive disorder have an all-cause mortality nearly 2.2-fold higher than their peers with non–treatment-resistant major depression.
Data source: This retrospective cohort study used Swedish national databases to look at all-cause mortality in more than 127,000 adults under psychiatric care for major depressive disorder.
Disclosures: The study was supported by Janssen. The presenter reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.