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Insurance-mandated diet pre–bariatric surgery deemed harmful
NEW ORLEANS – The widespread health insurance industry practice of requiring obese patients to spend months on a physician-supervised strict weight-loss diet prior to approving coverage of bariatric surgery accomplishes nothing constructive, Charles J. Keith Jr., MD, reported at Obesity Week 2016.
“We found that insurance-mandated preoperative diets were associated with a significant delay in treatment, no improvement in postoperative complication rates, and also no improvement in weight loss outcomes. If anything, after adjusting for potential confounding variables, the outcomes were inferior to the group that wasn’t required to diet,” said Dr. Keith of the University of Alabama at Birmingham.
Dr. Keith presented a retrospective review from the prospectively collected Alabama University bariatric surgery database, which included all 284 patients who underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy during 2009-2013. A total of 79% of the patients had private health insurance that required their participation in a preoperative physician-guided diet program, typically for 6 months. The other 21% did not have a mandatory preoperative diet requirement; the great majority of this group were covered under Medicare, which doesn’t require a diet program before bariatric surgery. The two groups weren’t significantly different in initial or immediately preoperative weight or body mass index, obesity-related comorbid conditions, type of bariatric surgery, or socioeconomic status.
The mean time from initial clinic visit to bariatric surgery was significantly shorter in the group with no mandated preoperative diet, at 154 vs. 218 days. In a multivariate analysis adjusted for age, sex, race, operation type, and comorbidities, the no-mandatory-diet group had a significantly greater reduction in BMI 6 months post surgery: a mean loss of 12.2 kg/m2, compared with 10.9 kg/m2 in the group required to participate in a preoperative diet. The difference was even greater at 2 years follow-up: a mean decrease of 14.9 kg/m2 in the no-diet group, vs. 10.7 kg/m2 in the mandatory diet group. The no-diet group experienced a mean 33% weight loss at 2 years, significantly better than the 25% weight loss in the mandatory diet group, Dr. Keith reported at the meeting, presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.
Audience discussion showed that the insurance-mandated preoperative diet requirement is a hot button issue in the bariatric surgical community.
“I think these insurance programs are specifically designed to delay care,” one surgeon asserted.
Another bariatric surgeon commented that while Dr. Keith’s study will be helpful in advocating for removal of the mandatory preoperative diet requirement, what’s really needed are studies that demonstrate just how often this requirement results in drop out from bariatric programs by patients who’ve grown discouraged by yet-another unsuccessful attempt at nonsurgical weight loss.
Dr. Keith reported having no financial conflicts of interest regarding his study.
NEW ORLEANS – The widespread health insurance industry practice of requiring obese patients to spend months on a physician-supervised strict weight-loss diet prior to approving coverage of bariatric surgery accomplishes nothing constructive, Charles J. Keith Jr., MD, reported at Obesity Week 2016.
“We found that insurance-mandated preoperative diets were associated with a significant delay in treatment, no improvement in postoperative complication rates, and also no improvement in weight loss outcomes. If anything, after adjusting for potential confounding variables, the outcomes were inferior to the group that wasn’t required to diet,” said Dr. Keith of the University of Alabama at Birmingham.
Dr. Keith presented a retrospective review from the prospectively collected Alabama University bariatric surgery database, which included all 284 patients who underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy during 2009-2013. A total of 79% of the patients had private health insurance that required their participation in a preoperative physician-guided diet program, typically for 6 months. The other 21% did not have a mandatory preoperative diet requirement; the great majority of this group were covered under Medicare, which doesn’t require a diet program before bariatric surgery. The two groups weren’t significantly different in initial or immediately preoperative weight or body mass index, obesity-related comorbid conditions, type of bariatric surgery, or socioeconomic status.
The mean time from initial clinic visit to bariatric surgery was significantly shorter in the group with no mandated preoperative diet, at 154 vs. 218 days. In a multivariate analysis adjusted for age, sex, race, operation type, and comorbidities, the no-mandatory-diet group had a significantly greater reduction in BMI 6 months post surgery: a mean loss of 12.2 kg/m2, compared with 10.9 kg/m2 in the group required to participate in a preoperative diet. The difference was even greater at 2 years follow-up: a mean decrease of 14.9 kg/m2 in the no-diet group, vs. 10.7 kg/m2 in the mandatory diet group. The no-diet group experienced a mean 33% weight loss at 2 years, significantly better than the 25% weight loss in the mandatory diet group, Dr. Keith reported at the meeting, presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.
Audience discussion showed that the insurance-mandated preoperative diet requirement is a hot button issue in the bariatric surgical community.
“I think these insurance programs are specifically designed to delay care,” one surgeon asserted.
Another bariatric surgeon commented that while Dr. Keith’s study will be helpful in advocating for removal of the mandatory preoperative diet requirement, what’s really needed are studies that demonstrate just how often this requirement results in drop out from bariatric programs by patients who’ve grown discouraged by yet-another unsuccessful attempt at nonsurgical weight loss.
Dr. Keith reported having no financial conflicts of interest regarding his study.
NEW ORLEANS – The widespread health insurance industry practice of requiring obese patients to spend months on a physician-supervised strict weight-loss diet prior to approving coverage of bariatric surgery accomplishes nothing constructive, Charles J. Keith Jr., MD, reported at Obesity Week 2016.
“We found that insurance-mandated preoperative diets were associated with a significant delay in treatment, no improvement in postoperative complication rates, and also no improvement in weight loss outcomes. If anything, after adjusting for potential confounding variables, the outcomes were inferior to the group that wasn’t required to diet,” said Dr. Keith of the University of Alabama at Birmingham.
Dr. Keith presented a retrospective review from the prospectively collected Alabama University bariatric surgery database, which included all 284 patients who underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy during 2009-2013. A total of 79% of the patients had private health insurance that required their participation in a preoperative physician-guided diet program, typically for 6 months. The other 21% did not have a mandatory preoperative diet requirement; the great majority of this group were covered under Medicare, which doesn’t require a diet program before bariatric surgery. The two groups weren’t significantly different in initial or immediately preoperative weight or body mass index, obesity-related comorbid conditions, type of bariatric surgery, or socioeconomic status.
The mean time from initial clinic visit to bariatric surgery was significantly shorter in the group with no mandated preoperative diet, at 154 vs. 218 days. In a multivariate analysis adjusted for age, sex, race, operation type, and comorbidities, the no-mandatory-diet group had a significantly greater reduction in BMI 6 months post surgery: a mean loss of 12.2 kg/m2, compared with 10.9 kg/m2 in the group required to participate in a preoperative diet. The difference was even greater at 2 years follow-up: a mean decrease of 14.9 kg/m2 in the no-diet group, vs. 10.7 kg/m2 in the mandatory diet group. The no-diet group experienced a mean 33% weight loss at 2 years, significantly better than the 25% weight loss in the mandatory diet group, Dr. Keith reported at the meeting, presented by the Obesity Society of America and the American Society for Metabolic and Bariatric Surgery.
Audience discussion showed that the insurance-mandated preoperative diet requirement is a hot button issue in the bariatric surgical community.
“I think these insurance programs are specifically designed to delay care,” one surgeon asserted.
Another bariatric surgeon commented that while Dr. Keith’s study will be helpful in advocating for removal of the mandatory preoperative diet requirement, what’s really needed are studies that demonstrate just how often this requirement results in drop out from bariatric programs by patients who’ve grown discouraged by yet-another unsuccessful attempt at nonsurgical weight loss.
Dr. Keith reported having no financial conflicts of interest regarding his study.
Key clinical point:
Major finding: At follow-up 2 years after bariatric surgery, patients who were required by their insurance company to participate in a physician-supervised preoperative diet program had an adjusted mean 25% weight loss, a significantly worse outcome than the mean 33% weight loss among patients with no such requirement.
Data source: This was a retrospective analysis of 284 patients in a prospectively collected university bariatric surgery database.
Disclosures: The study presenter reported having no relevant financial interests.
MDMA – the love drug – makes a therapeutic comeback
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology. 
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task. 
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
Teens see marijuana as less harmful after legalization
The legalization of recreational marijuana use is associated with an increase in use of the drug among adolescents, who also perceive it as being less harmful, a new study published online suggests.
In the study, Magdalena Cerdá, DrPH, MPH, and her associates used data from the Monitoring the Future study – a national, annual, cross-sectional survey conducted by the University of Michigan, Ann Arbor, that looks at attitudes about drug use among students in 8th, 10th, and 12th grade. The investigators analyzed the data gathered from 2010 to 2015 in an effort to compare attitudes about marijuana and its use before and after legalization in Washington and Colorado, and in states that did not legalize.
“While the increase in marijuana use among 8th graders in Washington was not significantly greater than zero, the significant decrease in use among 8th graders in states [with no recreational marijuana laws] suggests that if there had been no legalization in Washington, then marijuana use among 8th graders in this state would decrease rather than remain stable, as it did,” wrote Dr. Cerdà of the emergency medicine department at the University of California, Davis, in Sacramento, and her coauthors. “Specifically, the prevalence of regular users of marijuana increased and the prevalence of nonusers decreased; no change was observed among occasional users.”
Legalization, however, did not appear to significantly affect perceived harmfulness or use among 12th graders in any states, nor were there any significant changes after legalization among adolescents in all three grades surveyed in Colorado.
The authors noted that Colorado had a well-developed medical marijuana program in place, with substantial advertising, which might account for the lack of apparent impact of legalization for recreational use.
Commenting on the overall impact of legalization on use, the authors suggested that, besides reducing stigma and perceptions of risk, the legalization of recreational marijuana might have increased availability and potentially decreased the price, which might have led to the increase in use.
Given this, they cautiously proposed increased investment in evidence-based adolescent substance use prevention programs in states that choose to legalize recreational marijuana.
Dr. Cerdá and her associates cited several limitations. For example, the use of marijuana was self reported, and the Monitoring the Future results might have missed adolescents who were either absent from school when the survey was taken or had dropped out.
The study was supported by the National Institute on Drug Abuse, the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, and the New York State Psychiatric Institute. No conflicts of interest were declared.
The legalization of marijuana complicates efforts to prevent use of the drug by young people, Wayne Hall, PhD, and Megan Weier wrote in an accompanying editorial (JAMA Pediatr. 2016 Dec 27. doi: 10.1001/jamapediatrics.2016.3917).
“The challenge for health educators will be in acknowledging that the acute adverse effects of marijuana use are modest by comparison with those of alcohol or heroin, while persuading young people that they can experience adverse effects, especially if they begin use in their teens and use daily throughout young adult life,” Dr. Hall and Ms. Weir wrote.
Users of the drug, they said, should be told that the risk of a collision while driving while intoxicated doubles, “especially if they use both alcohol and marijuana.” In addition, Dr. Hall and Ms. Weier said, people who use the drug regularly should be informed that they can become dependent. “The risk for dependence is about 1 in 10 for those who ever use marijuana and 1 in 6 for those who first use in adolescence. Marijuana users also need to know that dependent users have more anxiety, depression, and psychotic disorders and are more likely to leave school early, to be unemployed as adults, and experience downward social mobility in mid-adulthood,” they wrote.
Dr. Hall and Ms. Weier are affiliated with the Centre for Youth Substance Abuse Research at Royal Brisbane and Women’s Hospital in Herston, Australia. They reported no conflicts of interest.
The legalization of marijuana complicates efforts to prevent use of the drug by young people, Wayne Hall, PhD, and Megan Weier wrote in an accompanying editorial (JAMA Pediatr. 2016 Dec 27. doi: 10.1001/jamapediatrics.2016.3917).
“The challenge for health educators will be in acknowledging that the acute adverse effects of marijuana use are modest by comparison with those of alcohol or heroin, while persuading young people that they can experience adverse effects, especially if they begin use in their teens and use daily throughout young adult life,” Dr. Hall and Ms. Weir wrote.
Users of the drug, they said, should be told that the risk of a collision while driving while intoxicated doubles, “especially if they use both alcohol and marijuana.” In addition, Dr. Hall and Ms. Weier said, people who use the drug regularly should be informed that they can become dependent. “The risk for dependence is about 1 in 10 for those who ever use marijuana and 1 in 6 for those who first use in adolescence. Marijuana users also need to know that dependent users have more anxiety, depression, and psychotic disorders and are more likely to leave school early, to be unemployed as adults, and experience downward social mobility in mid-adulthood,” they wrote.
Dr. Hall and Ms. Weier are affiliated with the Centre for Youth Substance Abuse Research at Royal Brisbane and Women’s Hospital in Herston, Australia. They reported no conflicts of interest.
The legalization of marijuana complicates efforts to prevent use of the drug by young people, Wayne Hall, PhD, and Megan Weier wrote in an accompanying editorial (JAMA Pediatr. 2016 Dec 27. doi: 10.1001/jamapediatrics.2016.3917).
“The challenge for health educators will be in acknowledging that the acute adverse effects of marijuana use are modest by comparison with those of alcohol or heroin, while persuading young people that they can experience adverse effects, especially if they begin use in their teens and use daily throughout young adult life,” Dr. Hall and Ms. Weir wrote.
Users of the drug, they said, should be told that the risk of a collision while driving while intoxicated doubles, “especially if they use both alcohol and marijuana.” In addition, Dr. Hall and Ms. Weier said, people who use the drug regularly should be informed that they can become dependent. “The risk for dependence is about 1 in 10 for those who ever use marijuana and 1 in 6 for those who first use in adolescence. Marijuana users also need to know that dependent users have more anxiety, depression, and psychotic disorders and are more likely to leave school early, to be unemployed as adults, and experience downward social mobility in mid-adulthood,” they wrote.
Dr. Hall and Ms. Weier are affiliated with the Centre for Youth Substance Abuse Research at Royal Brisbane and Women’s Hospital in Herston, Australia. They reported no conflicts of interest.
The legalization of recreational marijuana use is associated with an increase in use of the drug among adolescents, who also perceive it as being less harmful, a new study published online suggests.
In the study, Magdalena Cerdá, DrPH, MPH, and her associates used data from the Monitoring the Future study – a national, annual, cross-sectional survey conducted by the University of Michigan, Ann Arbor, that looks at attitudes about drug use among students in 8th, 10th, and 12th grade. The investigators analyzed the data gathered from 2010 to 2015 in an effort to compare attitudes about marijuana and its use before and after legalization in Washington and Colorado, and in states that did not legalize.
“While the increase in marijuana use among 8th graders in Washington was not significantly greater than zero, the significant decrease in use among 8th graders in states [with no recreational marijuana laws] suggests that if there had been no legalization in Washington, then marijuana use among 8th graders in this state would decrease rather than remain stable, as it did,” wrote Dr. Cerdà of the emergency medicine department at the University of California, Davis, in Sacramento, and her coauthors. “Specifically, the prevalence of regular users of marijuana increased and the prevalence of nonusers decreased; no change was observed among occasional users.”
Legalization, however, did not appear to significantly affect perceived harmfulness or use among 12th graders in any states, nor were there any significant changes after legalization among adolescents in all three grades surveyed in Colorado.
The authors noted that Colorado had a well-developed medical marijuana program in place, with substantial advertising, which might account for the lack of apparent impact of legalization for recreational use.
Commenting on the overall impact of legalization on use, the authors suggested that, besides reducing stigma and perceptions of risk, the legalization of recreational marijuana might have increased availability and potentially decreased the price, which might have led to the increase in use.
Given this, they cautiously proposed increased investment in evidence-based adolescent substance use prevention programs in states that choose to legalize recreational marijuana.
Dr. Cerdá and her associates cited several limitations. For example, the use of marijuana was self reported, and the Monitoring the Future results might have missed adolescents who were either absent from school when the survey was taken or had dropped out.
The study was supported by the National Institute on Drug Abuse, the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, and the New York State Psychiatric Institute. No conflicts of interest were declared.
The legalization of recreational marijuana use is associated with an increase in use of the drug among adolescents, who also perceive it as being less harmful, a new study published online suggests.
In the study, Magdalena Cerdá, DrPH, MPH, and her associates used data from the Monitoring the Future study – a national, annual, cross-sectional survey conducted by the University of Michigan, Ann Arbor, that looks at attitudes about drug use among students in 8th, 10th, and 12th grade. The investigators analyzed the data gathered from 2010 to 2015 in an effort to compare attitudes about marijuana and its use before and after legalization in Washington and Colorado, and in states that did not legalize.
“While the increase in marijuana use among 8th graders in Washington was not significantly greater than zero, the significant decrease in use among 8th graders in states [with no recreational marijuana laws] suggests that if there had been no legalization in Washington, then marijuana use among 8th graders in this state would decrease rather than remain stable, as it did,” wrote Dr. Cerdà of the emergency medicine department at the University of California, Davis, in Sacramento, and her coauthors. “Specifically, the prevalence of regular users of marijuana increased and the prevalence of nonusers decreased; no change was observed among occasional users.”
Legalization, however, did not appear to significantly affect perceived harmfulness or use among 12th graders in any states, nor were there any significant changes after legalization among adolescents in all three grades surveyed in Colorado.
The authors noted that Colorado had a well-developed medical marijuana program in place, with substantial advertising, which might account for the lack of apparent impact of legalization for recreational use.
Commenting on the overall impact of legalization on use, the authors suggested that, besides reducing stigma and perceptions of risk, the legalization of recreational marijuana might have increased availability and potentially decreased the price, which might have led to the increase in use.
Given this, they cautiously proposed increased investment in evidence-based adolescent substance use prevention programs in states that choose to legalize recreational marijuana.
Dr. Cerdá and her associates cited several limitations. For example, the use of marijuana was self reported, and the Monitoring the Future results might have missed adolescents who were either absent from school when the survey was taken or had dropped out.
The study was supported by the National Institute on Drug Abuse, the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, and the New York State Psychiatric Institute. No conflicts of interest were declared.
Key clinical point: The legalization of recreational marijuana use is associated with an increase in its use among adolescents, who also perceive it as being less harmful.
Major finding: The perceived harmfulness of marijuana declined by 14.2% among 8th graders and 16.1% among 10th graders after legalization in Washington, compared with 4.9% and 7.1% decreases among 8th and 10th graders in states that did not legalize.
Data source: The Monitoring the Future study is a national, annual, cross-sectional survey of 253,902 students in the 8th, 10th, and 12th grades.
Disclosures: The study was supported by the National Institute on Drug Abuse, the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, and the New York State Psychiatric Institute. No conflicts of interest were declared.
Combo improves survival in newly diagnosed MM
Photo courtesy of
Millenium Pharmaceuticals
Results of a phase 3 trial suggest a 3-drug combination improves survival in newly diagnosed multiple myeloma (MM).
The trial showed that bortezomib, lenalidomide, and dexamethasone (VRd) could significantly
improve progression-free and overall survival when compared to lenalidomide and dexamethasone (Rd).
In addition, investigators said the risk-benefit profile of VRd was acceptable.
The team noted, however, that grade 3 or higher neurologic adverse events (AEs) were more common with VRd than with Rd.
“Our results are clear,” said principal investigator Brian G.M. Durie, MD, of Cedars-Sinai Outpatient Cancer Center in Los Angeles, California.
“Using bortezomib in combination with lenalidomide and dexamethasone in frontline treatment—hitting the disease early and hard—makes a meaningful difference for myeloma patients. Our results represent a potential new standard of care.”
Dr Durie and his colleagues reported the results of this trial in The Lancet.
The research was funded by Millennium Pharmaceuticals, Takeda Oncology Company, Celgene Corporation, the National Institutes of Health, the National Cancer Institute, and the National Clinical Trial Network.
The trial enrolled 525 adults with MM. The patients ranged in age from 28 to 87, had active MM, and had not had any prior treatment for their disease.
The patients were randomized to 2 treatment groups. One group received Rd for 6 cycles over 6 months. The other group received VRd for 8 cycles over 6 months.
Results
The median follow-up was 55 months. In the VRd group, 241 patients were evaluable for safety and 216 for response. In the Rd group, 226 patients were evaluable for safety and 214 for response.
The overall response rate was 82% (176/216) in the VRd group and 72% (153/214) in the Rd group. The complete response rates were 16% (34/216) and 8% (18/214), respectively.
The median progression-free survival was 43 months in the VRd group and 30 months in the Rd group. The hazard ratio was 0.712 (P=0.0018).
The median overall survival was 75 months in the VRd group and 64 months in the Rd group. The hazard ratio was 0.709 (P=0.025).
The rate of grade 3 or higher AEs was 82% in the VRd group and 75% in the Rd group. The rate of discontinuation due to AEs was 23% and 10%, respectively.
Grade 3 or higher neurologic AEs were more frequent in the VRd group than in the Rd group—33% and 11%, respectively (P<0.0001).
There were 2 treatment-related deaths in the VRd group but none in the Rd group. And 10 patients in each group had a second primary malignancy.
“This is a landmark study that lends clarity to frontline therapy of myeloma,” said study author S. Vincent Rajkumar, MD, of Mayo Clinic in Rochester, Minnesota.
“Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials.”
Also worth noting, Dr Rajkumar said, is that the VRd regimen will become even more cost-effective as the drugs in this combination become generic over time. 
Photo courtesy of
Millenium Pharmaceuticals
Results of a phase 3 trial suggest a 3-drug combination improves survival in newly diagnosed multiple myeloma (MM).
The trial showed that bortezomib, lenalidomide, and dexamethasone (VRd) could significantly
improve progression-free and overall survival when compared to lenalidomide and dexamethasone (Rd).
In addition, investigators said the risk-benefit profile of VRd was acceptable.
The team noted, however, that grade 3 or higher neurologic adverse events (AEs) were more common with VRd than with Rd.
“Our results are clear,” said principal investigator Brian G.M. Durie, MD, of Cedars-Sinai Outpatient Cancer Center in Los Angeles, California.
“Using bortezomib in combination with lenalidomide and dexamethasone in frontline treatment—hitting the disease early and hard—makes a meaningful difference for myeloma patients. Our results represent a potential new standard of care.”
Dr Durie and his colleagues reported the results of this trial in The Lancet.
The research was funded by Millennium Pharmaceuticals, Takeda Oncology Company, Celgene Corporation, the National Institutes of Health, the National Cancer Institute, and the National Clinical Trial Network.
The trial enrolled 525 adults with MM. The patients ranged in age from 28 to 87, had active MM, and had not had any prior treatment for their disease.
The patients were randomized to 2 treatment groups. One group received Rd for 6 cycles over 6 months. The other group received VRd for 8 cycles over 6 months.
Results
The median follow-up was 55 months. In the VRd group, 241 patients were evaluable for safety and 216 for response. In the Rd group, 226 patients were evaluable for safety and 214 for response.
The overall response rate was 82% (176/216) in the VRd group and 72% (153/214) in the Rd group. The complete response rates were 16% (34/216) and 8% (18/214), respectively.
The median progression-free survival was 43 months in the VRd group and 30 months in the Rd group. The hazard ratio was 0.712 (P=0.0018).
The median overall survival was 75 months in the VRd group and 64 months in the Rd group. The hazard ratio was 0.709 (P=0.025).
The rate of grade 3 or higher AEs was 82% in the VRd group and 75% in the Rd group. The rate of discontinuation due to AEs was 23% and 10%, respectively.
Grade 3 or higher neurologic AEs were more frequent in the VRd group than in the Rd group—33% and 11%, respectively (P<0.0001).
There were 2 treatment-related deaths in the VRd group but none in the Rd group. And 10 patients in each group had a second primary malignancy.
“This is a landmark study that lends clarity to frontline therapy of myeloma,” said study author S. Vincent Rajkumar, MD, of Mayo Clinic in Rochester, Minnesota.
“Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials.”
Also worth noting, Dr Rajkumar said, is that the VRd regimen will become even more cost-effective as the drugs in this combination become generic over time.
Photo courtesy of
Millenium Pharmaceuticals
Results of a phase 3 trial suggest a 3-drug combination improves survival in newly diagnosed multiple myeloma (MM).
The trial showed that bortezomib, lenalidomide, and dexamethasone (VRd) could significantly
improve progression-free and overall survival when compared to lenalidomide and dexamethasone (Rd).
In addition, investigators said the risk-benefit profile of VRd was acceptable.
The team noted, however, that grade 3 or higher neurologic adverse events (AEs) were more common with VRd than with Rd.
“Our results are clear,” said principal investigator Brian G.M. Durie, MD, of Cedars-Sinai Outpatient Cancer Center in Los Angeles, California.
“Using bortezomib in combination with lenalidomide and dexamethasone in frontline treatment—hitting the disease early and hard—makes a meaningful difference for myeloma patients. Our results represent a potential new standard of care.”
Dr Durie and his colleagues reported the results of this trial in The Lancet.
The research was funded by Millennium Pharmaceuticals, Takeda Oncology Company, Celgene Corporation, the National Institutes of Health, the National Cancer Institute, and the National Clinical Trial Network.
The trial enrolled 525 adults with MM. The patients ranged in age from 28 to 87, had active MM, and had not had any prior treatment for their disease.
The patients were randomized to 2 treatment groups. One group received Rd for 6 cycles over 6 months. The other group received VRd for 8 cycles over 6 months.
Results
The median follow-up was 55 months. In the VRd group, 241 patients were evaluable for safety and 216 for response. In the Rd group, 226 patients were evaluable for safety and 214 for response.
The overall response rate was 82% (176/216) in the VRd group and 72% (153/214) in the Rd group. The complete response rates were 16% (34/216) and 8% (18/214), respectively.
The median progression-free survival was 43 months in the VRd group and 30 months in the Rd group. The hazard ratio was 0.712 (P=0.0018).
The median overall survival was 75 months in the VRd group and 64 months in the Rd group. The hazard ratio was 0.709 (P=0.025).
The rate of grade 3 or higher AEs was 82% in the VRd group and 75% in the Rd group. The rate of discontinuation due to AEs was 23% and 10%, respectively.
Grade 3 or higher neurologic AEs were more frequent in the VRd group than in the Rd group—33% and 11%, respectively (P<0.0001).
There were 2 treatment-related deaths in the VRd group but none in the Rd group. And 10 patients in each group had a second primary malignancy.
“This is a landmark study that lends clarity to frontline therapy of myeloma,” said study author S. Vincent Rajkumar, MD, of Mayo Clinic in Rochester, Minnesota.
“Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials.”
Also worth noting, Dr Rajkumar said, is that the VRd regimen will become even more cost-effective as the drugs in this combination become generic over time.
Company withdraws MAA for biosimilar pegfilgrastim
Image by Volker Brinkmann
Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).
Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).
The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.
The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.
Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).
Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.
After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.
Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.
The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.
In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.
Image by Volker Brinkmann
Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).
Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).
The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.
The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.
Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).
Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.
After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.
Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.
The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.
In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.
Image by Volker Brinkmann
Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).
Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).
The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.
The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.
Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).
Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.
After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.
Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.
The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.
In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.
Drug can improve upon chelation therapy in thalassemia major
An anti-hypertensive drug can improve the effects of chelation therapy in patients with thalassemia major and cardiac iron overload, according to research published in Blood.
Researchers found that administering the drug, amlodipine, in conjunction with conventional chelation therapy significantly reduced myocardial iron concentration (MIC) in patients with cardiac iron overload at baseline, when compared to chelation therapy alone.
In addition, amlodipine did not cause any serious adverse events.
“The drug has been used clinically for decades and is considered safe for adults and children,” said study author Juliano de Lara Fernandes, MD, PhD, of José Michel Kalaf Research Institute in Campinas, São Paulo State, Brazil.
“As an adjunct to standard treatment, it can be greatly beneficial to patients and has few side effects.”
Dr Fernandes said he and his colleagues decided to test amlodipine in patients with thalassemia major because although chelation therapy works well in peripheral organs, it’s difficult to remove iron from the heart.
“Myocardial dysfunctions are currently the main cause of death among patients with thalassemia and can emerge in children from the age of 10,” Dr Fernandes said.
The most serious problem of all, he added, is caused by an accumulation of non-transferrin bound iron (NTBI) in myocardial cells. NTBI enters and leaves the liver without causing much damage to the organ, but it enters the heart via a channel whose main role is to carry calcium into cells.
“It occurred to us that drugs capable of blocking the calcium channel could also prevent NTBI from entering the heart and therefore increase the efficacy of chelation therapy,” Dr Fernandes said.
He and his colleagues tested this hypothesis in 62 patients with thalassemia major. The patients were divided into 2 treatment groups. One group received conventional chelation therapy along with amlodipine (5 mg/day), and the other received chelation therapy plus oral placebo.
Patients were further divided according to cardiac iron levels at baseline. Cardiac iron overload was defined as T2* < 35 ms. Fifty percent of patients in the amlodipine arm and 52% of those in the placebo arm had cardiac iron overload at baseline.
Results
The study’s main outcome was change in MIC, as determined by magnetic resonance imaging at 12 months.
At that point, among patients with cardiac iron overload at baseline, there was a significant decrease in MIC in the amlodipine arm but not the placebo arm. The median change in MIC was -0.26 mg/g and 0.01 mg/g, respectively (P=0.02).
The median MIC in the amlodipine arm went from 1.31 mg/g at baseline to 1.05 mg/g at 12 months (P=0.02). The median MIC in the placebo arm went from 0.77 mg/g at baseline to 0.75 at 12 months (P=0.76).
“Myocardial iron concentration fell 21% in patients with initial iron overload who were treated with chelation plus amlodipine, whereas it increased by 2% in those with initial overload who were treated with chelation plus placebo,” Dr Fernandes said.
On the other hand, there were no significant differences in MIC from baseline to 12 months among patients who received amlodipine but did not have cardiac iron overload at baseline.
For patients without cardiac iron overload at baseline, the median change in MIC was +0.04 mg/g in the amlodipine arm and -0.01 in the placebo arm (P=0.07).
The median MIC in the amlodipine arm went from 0.54 mg/g at baseline to 0.55 mg/g at 12 months. The median MIC in the placebo arm went from 0.55 mg/g at baseline to 0.52 mg/g at 12 months.
“Perhaps we would have needed to monitor these patients for a longer period to see the benefits of preventive therapy with amlodipine for people who don’t have excess iron in their organs,” Dr Fernandes said.
“For those who do, however, the results show it’s worth using amlodipine. There’s no need to change the existing therapy. It’s enough to administer the anti-hypertensive orally every day.”
There were 4 mild adverse events in the amlodipine arm but none in the placebo arm (13% vs 0%, P=0.11).
Three patients (10%) in the amlodipine arm had their initial dose of 5 mg/day reduced to 2.5 mg/day because of mild ankle edema (n=2) and dizziness (n=1). One patient had a mild cutaneous allergic reaction and stopped receiving amlodipine after 15 days but continued on study.
There were no deaths or hospital admissions due to cardiovascular complications during the trial.
An anti-hypertensive drug can improve the effects of chelation therapy in patients with thalassemia major and cardiac iron overload, according to research published in Blood.
Researchers found that administering the drug, amlodipine, in conjunction with conventional chelation therapy significantly reduced myocardial iron concentration (MIC) in patients with cardiac iron overload at baseline, when compared to chelation therapy alone.
In addition, amlodipine did not cause any serious adverse events.
“The drug has been used clinically for decades and is considered safe for adults and children,” said study author Juliano de Lara Fernandes, MD, PhD, of José Michel Kalaf Research Institute in Campinas, São Paulo State, Brazil.
“As an adjunct to standard treatment, it can be greatly beneficial to patients and has few side effects.”
Dr Fernandes said he and his colleagues decided to test amlodipine in patients with thalassemia major because although chelation therapy works well in peripheral organs, it’s difficult to remove iron from the heart.
“Myocardial dysfunctions are currently the main cause of death among patients with thalassemia and can emerge in children from the age of 10,” Dr Fernandes said.
The most serious problem of all, he added, is caused by an accumulation of non-transferrin bound iron (NTBI) in myocardial cells. NTBI enters and leaves the liver without causing much damage to the organ, but it enters the heart via a channel whose main role is to carry calcium into cells.
“It occurred to us that drugs capable of blocking the calcium channel could also prevent NTBI from entering the heart and therefore increase the efficacy of chelation therapy,” Dr Fernandes said.
He and his colleagues tested this hypothesis in 62 patients with thalassemia major. The patients were divided into 2 treatment groups. One group received conventional chelation therapy along with amlodipine (5 mg/day), and the other received chelation therapy plus oral placebo.
Patients were further divided according to cardiac iron levels at baseline. Cardiac iron overload was defined as T2* < 35 ms. Fifty percent of patients in the amlodipine arm and 52% of those in the placebo arm had cardiac iron overload at baseline.
Results
The study’s main outcome was change in MIC, as determined by magnetic resonance imaging at 12 months.
At that point, among patients with cardiac iron overload at baseline, there was a significant decrease in MIC in the amlodipine arm but not the placebo arm. The median change in MIC was -0.26 mg/g and 0.01 mg/g, respectively (P=0.02).
The median MIC in the amlodipine arm went from 1.31 mg/g at baseline to 1.05 mg/g at 12 months (P=0.02). The median MIC in the placebo arm went from 0.77 mg/g at baseline to 0.75 at 12 months (P=0.76).
“Myocardial iron concentration fell 21% in patients with initial iron overload who were treated with chelation plus amlodipine, whereas it increased by 2% in those with initial overload who were treated with chelation plus placebo,” Dr Fernandes said.
On the other hand, there were no significant differences in MIC from baseline to 12 months among patients who received amlodipine but did not have cardiac iron overload at baseline.
For patients without cardiac iron overload at baseline, the median change in MIC was +0.04 mg/g in the amlodipine arm and -0.01 in the placebo arm (P=0.07).
The median MIC in the amlodipine arm went from 0.54 mg/g at baseline to 0.55 mg/g at 12 months. The median MIC in the placebo arm went from 0.55 mg/g at baseline to 0.52 mg/g at 12 months.
“Perhaps we would have needed to monitor these patients for a longer period to see the benefits of preventive therapy with amlodipine for people who don’t have excess iron in their organs,” Dr Fernandes said.
“For those who do, however, the results show it’s worth using amlodipine. There’s no need to change the existing therapy. It’s enough to administer the anti-hypertensive orally every day.”
There were 4 mild adverse events in the amlodipine arm but none in the placebo arm (13% vs 0%, P=0.11).
Three patients (10%) in the amlodipine arm had their initial dose of 5 mg/day reduced to 2.5 mg/day because of mild ankle edema (n=2) and dizziness (n=1). One patient had a mild cutaneous allergic reaction and stopped receiving amlodipine after 15 days but continued on study.
There were no deaths or hospital admissions due to cardiovascular complications during the trial.
An anti-hypertensive drug can improve the effects of chelation therapy in patients with thalassemia major and cardiac iron overload, according to research published in Blood.
Researchers found that administering the drug, amlodipine, in conjunction with conventional chelation therapy significantly reduced myocardial iron concentration (MIC) in patients with cardiac iron overload at baseline, when compared to chelation therapy alone.
In addition, amlodipine did not cause any serious adverse events.
“The drug has been used clinically for decades and is considered safe for adults and children,” said study author Juliano de Lara Fernandes, MD, PhD, of José Michel Kalaf Research Institute in Campinas, São Paulo State, Brazil.
“As an adjunct to standard treatment, it can be greatly beneficial to patients and has few side effects.”
Dr Fernandes said he and his colleagues decided to test amlodipine in patients with thalassemia major because although chelation therapy works well in peripheral organs, it’s difficult to remove iron from the heart.
“Myocardial dysfunctions are currently the main cause of death among patients with thalassemia and can emerge in children from the age of 10,” Dr Fernandes said.
The most serious problem of all, he added, is caused by an accumulation of non-transferrin bound iron (NTBI) in myocardial cells. NTBI enters and leaves the liver without causing much damage to the organ, but it enters the heart via a channel whose main role is to carry calcium into cells.
“It occurred to us that drugs capable of blocking the calcium channel could also prevent NTBI from entering the heart and therefore increase the efficacy of chelation therapy,” Dr Fernandes said.
He and his colleagues tested this hypothesis in 62 patients with thalassemia major. The patients were divided into 2 treatment groups. One group received conventional chelation therapy along with amlodipine (5 mg/day), and the other received chelation therapy plus oral placebo.
Patients were further divided according to cardiac iron levels at baseline. Cardiac iron overload was defined as T2* < 35 ms. Fifty percent of patients in the amlodipine arm and 52% of those in the placebo arm had cardiac iron overload at baseline.
Results
The study’s main outcome was change in MIC, as determined by magnetic resonance imaging at 12 months.
At that point, among patients with cardiac iron overload at baseline, there was a significant decrease in MIC in the amlodipine arm but not the placebo arm. The median change in MIC was -0.26 mg/g and 0.01 mg/g, respectively (P=0.02).
The median MIC in the amlodipine arm went from 1.31 mg/g at baseline to 1.05 mg/g at 12 months (P=0.02). The median MIC in the placebo arm went from 0.77 mg/g at baseline to 0.75 at 12 months (P=0.76).
“Myocardial iron concentration fell 21% in patients with initial iron overload who were treated with chelation plus amlodipine, whereas it increased by 2% in those with initial overload who were treated with chelation plus placebo,” Dr Fernandes said.
On the other hand, there were no significant differences in MIC from baseline to 12 months among patients who received amlodipine but did not have cardiac iron overload at baseline.
For patients without cardiac iron overload at baseline, the median change in MIC was +0.04 mg/g in the amlodipine arm and -0.01 in the placebo arm (P=0.07).
The median MIC in the amlodipine arm went from 0.54 mg/g at baseline to 0.55 mg/g at 12 months. The median MIC in the placebo arm went from 0.55 mg/g at baseline to 0.52 mg/g at 12 months.
“Perhaps we would have needed to monitor these patients for a longer period to see the benefits of preventive therapy with amlodipine for people who don’t have excess iron in their organs,” Dr Fernandes said.
“For those who do, however, the results show it’s worth using amlodipine. There’s no need to change the existing therapy. It’s enough to administer the anti-hypertensive orally every day.”
There were 4 mild adverse events in the amlodipine arm but none in the placebo arm (13% vs 0%, P=0.11).
Three patients (10%) in the amlodipine arm had their initial dose of 5 mg/day reduced to 2.5 mg/day because of mild ankle edema (n=2) and dizziness (n=1). One patient had a mild cutaneous allergic reaction and stopped receiving amlodipine after 15 days but continued on study.
There were no deaths or hospital admissions due to cardiovascular complications during the trial.
Rash on top of feet
The FP suspected that contact dermatitis was to blame for the rash on the dorsum of the patient’s feet. This would have been an unlikely location for tinea pedis and the patient had already tried topical antifungal medications without any benefit. The FP asked the patient if he had purchased any new shoes or boots before the rash started, and the patient indicated that he’d purchased new running shoes about a year earlier.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily. The FP recognized that patch testing might be indicated, but did not perform this in her office. She also recommended that the patient stay away from the running shoes at this time. One month later, the rash was 95% better, except for some postinflammatory hyperpigmentation that was likely to take months to fade. The patient was happy with the results, but wanted to know the cause of his allergy and what shoes would be safe to wear.
The FP offered the patient a referral to a local dermatologist who performed patch testing. The patient went for patch testing and learned he was allergic to chromates found in many types of leather. Statistically, the most likely offending allergens for a rash in this location would be formaldehyde or a chromate. Both are found in leather and are common allergens that cause contact dermatitis on the feet.
Allergic contact dermatitis to chromate in leather shoes may be seasonal as a result of the allergen being leached out by perspiration in warmer months. There are leather shoes that are made free of chromates for people who suffer from allergic contact dermatitis due to this allergen.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The FP suspected that contact dermatitis was to blame for the rash on the dorsum of the patient’s feet. This would have been an unlikely location for tinea pedis and the patient had already tried topical antifungal medications without any benefit. The FP asked the patient if he had purchased any new shoes or boots before the rash started, and the patient indicated that he’d purchased new running shoes about a year earlier.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily. The FP recognized that patch testing might be indicated, but did not perform this in her office. She also recommended that the patient stay away from the running shoes at this time. One month later, the rash was 95% better, except for some postinflammatory hyperpigmentation that was likely to take months to fade. The patient was happy with the results, but wanted to know the cause of his allergy and what shoes would be safe to wear.
The FP offered the patient a referral to a local dermatologist who performed patch testing. The patient went for patch testing and learned he was allergic to chromates found in many types of leather. Statistically, the most likely offending allergens for a rash in this location would be formaldehyde or a chromate. Both are found in leather and are common allergens that cause contact dermatitis on the feet.
Allergic contact dermatitis to chromate in leather shoes may be seasonal as a result of the allergen being leached out by perspiration in warmer months. There are leather shoes that are made free of chromates for people who suffer from allergic contact dermatitis due to this allergen.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The FP suspected that contact dermatitis was to blame for the rash on the dorsum of the patient’s feet. This would have been an unlikely location for tinea pedis and the patient had already tried topical antifungal medications without any benefit. The FP asked the patient if he had purchased any new shoes or boots before the rash started, and the patient indicated that he’d purchased new running shoes about a year earlier.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily. The FP recognized that patch testing might be indicated, but did not perform this in her office. She also recommended that the patient stay away from the running shoes at this time. One month later, the rash was 95% better, except for some postinflammatory hyperpigmentation that was likely to take months to fade. The patient was happy with the results, but wanted to know the cause of his allergy and what shoes would be safe to wear.
The FP offered the patient a referral to a local dermatologist who performed patch testing. The patient went for patch testing and learned he was allergic to chromates found in many types of leather. Statistically, the most likely offending allergens for a rash in this location would be formaldehyde or a chromate. Both are found in leather and are common allergens that cause contact dermatitis on the feet.
Allergic contact dermatitis to chromate in leather shoes may be seasonal as a result of the allergen being leached out by perspiration in warmer months. There are leather shoes that are made free of chromates for people who suffer from allergic contact dermatitis due to this allergen.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Reppa R. Tinea pedis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:799-804.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
Hawaii continues to top ‘America’s Health Rankings’
2016 has been a year full of surprises, but not when it comes to the state leading “America’s Health Rankings.” For the fifth consecutive year, Hawaii has been named the healthiest state by the United Health Foundation’s annual report.
Also not a surprise was Mississippi’s 50th-place finish. The Magnolia State most recently finished last in 2014 and has never finished out of the bottom three in the annual ranking. Hawaii, on the other hand, has finished first eight times in the 27 years of the rankings – more than any other state – and has never finished out of the top six, according to the foundation’s 2016 report.
The other states ranked in the top five were well behind Hawaii’s score of 0.905 (representing the weighted standard deviation relative to the U.S. value): Massachusetts was second at 0.760, followed by Connecticut (0.747), Minnesota (0.727), and Vermont (0.709). Just above Mississippi’s score of –1.123 were Louisiana (–1.043), Arkansas (–0.834), Alabama (–0.793), and Oklahoma (–0.691), the foundation reported.
The report ranks states using 34 measures in five broad areas: behaviors, community and environment, policy, clinical care, and outcomes. Measures include drug death rate, air pollution, child immunization rate, preventable hospitalization rate, and premature death rate.
“America’s Health Rankings” is a joint effort by the United Health Foundation and the American Public Health Association. It is funded entirely by the private, not-for-profit United Health Foundation, founded by UnitedHealth Group, which operates UnitedHealthcare.
2016 has been a year full of surprises, but not when it comes to the state leading “America’s Health Rankings.” For the fifth consecutive year, Hawaii has been named the healthiest state by the United Health Foundation’s annual report.
Also not a surprise was Mississippi’s 50th-place finish. The Magnolia State most recently finished last in 2014 and has never finished out of the bottom three in the annual ranking. Hawaii, on the other hand, has finished first eight times in the 27 years of the rankings – more than any other state – and has never finished out of the top six, according to the foundation’s 2016 report.
The other states ranked in the top five were well behind Hawaii’s score of 0.905 (representing the weighted standard deviation relative to the U.S. value): Massachusetts was second at 0.760, followed by Connecticut (0.747), Minnesota (0.727), and Vermont (0.709). Just above Mississippi’s score of –1.123 were Louisiana (–1.043), Arkansas (–0.834), Alabama (–0.793), and Oklahoma (–0.691), the foundation reported.
The report ranks states using 34 measures in five broad areas: behaviors, community and environment, policy, clinical care, and outcomes. Measures include drug death rate, air pollution, child immunization rate, preventable hospitalization rate, and premature death rate.
“America’s Health Rankings” is a joint effort by the United Health Foundation and the American Public Health Association. It is funded entirely by the private, not-for-profit United Health Foundation, founded by UnitedHealth Group, which operates UnitedHealthcare.
2016 has been a year full of surprises, but not when it comes to the state leading “America’s Health Rankings.” For the fifth consecutive year, Hawaii has been named the healthiest state by the United Health Foundation’s annual report.
Also not a surprise was Mississippi’s 50th-place finish. The Magnolia State most recently finished last in 2014 and has never finished out of the bottom three in the annual ranking. Hawaii, on the other hand, has finished first eight times in the 27 years of the rankings – more than any other state – and has never finished out of the top six, according to the foundation’s 2016 report.
The other states ranked in the top five were well behind Hawaii’s score of 0.905 (representing the weighted standard deviation relative to the U.S. value): Massachusetts was second at 0.760, followed by Connecticut (0.747), Minnesota (0.727), and Vermont (0.709). Just above Mississippi’s score of –1.123 were Louisiana (–1.043), Arkansas (–0.834), Alabama (–0.793), and Oklahoma (–0.691), the foundation reported.
The report ranks states using 34 measures in five broad areas: behaviors, community and environment, policy, clinical care, and outcomes. Measures include drug death rate, air pollution, child immunization rate, preventable hospitalization rate, and premature death rate.
“America’s Health Rankings” is a joint effort by the United Health Foundation and the American Public Health Association. It is funded entirely by the private, not-for-profit United Health Foundation, founded by UnitedHealth Group, which operates UnitedHealthcare.
Which Patients With Epilepsy Can Safely Drive?
HOUSTON—Seizure duration and impaired consciousness may be important factors that affect driving performance, according to a study presented at the 70th Annual Meeting of the American Epilepsy Society. “With further work, we hope to … determine whether specific seizure types or localizations present a greater driving risk, with the goal of providing improved guidance to physicians and patients with epilepsy,” researchers said.
A lack of data about driving performance during ictal and postictal periods can make it difficult for physicians to determine whether patients can safely drive.
To study driving impairment during seizures, Hal Blumenfeld, MD, PhD, Director of the Yale Clinical Neuroscience Imaging Center in New Haven, Connecticut, and colleagues asked patients to perform a driving simulation test during inpatient video EEG monitoring. Dr. Blumenfeld, the study’s lead author, is the Mark Loughridge and Michele Williams Professor of Neurology and a Professor of Neuroscience and Neurosurgery at Yale University. 
The study included 20 patients who were observed in the epilepsy monitoring unit at Yale New Haven Hospital. Investigators analyzed ictal and interictal driving data captured prospectively from the driving simulator. A total of 33 seizures were analyzed. The investigators compared interictal and ictal driving performance through quantitative analysis. Variables included car velocity, steering wheel movement, braking, and crash occurrence.
Patients drove between one and 10 hours, with an average driving duration of about three hours. Patients had variable impairment during ictal and postictal periods and during subclinical epileptiform discharges. Some seizures showed obvious impairment, and others showed no change in driving performance. Seizures with driving impairment had significantly greater duration and were more likely to involve impaired consciousness than seizures without driving impairment. Seven of the seizures resulted in crashes. Seizures lasted an average of 75 seconds in patients who crashed, compared with an average of 30 seconds in patients who did not crash.
Driving simulations during inpatient video-EEG monitoring may be a useful way to determine factors that influence driving safety, the researchers concluded.
“It is going to take a lot more data to come up with a reliable way of predicting which people with epilepsy should drive and which should not,” said Dr. Blumenfeld. “We want to unearth more detail to learn if there are people with epilepsy who are driving who shouldn’t be, as well those who are not driving who can safely drive.”
HOUSTON—Seizure duration and impaired consciousness may be important factors that affect driving performance, according to a study presented at the 70th Annual Meeting of the American Epilepsy Society. “With further work, we hope to … determine whether specific seizure types or localizations present a greater driving risk, with the goal of providing improved guidance to physicians and patients with epilepsy,” researchers said.
A lack of data about driving performance during ictal and postictal periods can make it difficult for physicians to determine whether patients can safely drive.
To study driving impairment during seizures, Hal Blumenfeld, MD, PhD, Director of the Yale Clinical Neuroscience Imaging Center in New Haven, Connecticut, and colleagues asked patients to perform a driving simulation test during inpatient video EEG monitoring. Dr. Blumenfeld, the study’s lead author, is the Mark Loughridge and Michele Williams Professor of Neurology and a Professor of Neuroscience and Neurosurgery at Yale University.
The study included 20 patients who were observed in the epilepsy monitoring unit at Yale New Haven Hospital. Investigators analyzed ictal and interictal driving data captured prospectively from the driving simulator. A total of 33 seizures were analyzed. The investigators compared interictal and ictal driving performance through quantitative analysis. Variables included car velocity, steering wheel movement, braking, and crash occurrence.
Patients drove between one and 10 hours, with an average driving duration of about three hours. Patients had variable impairment during ictal and postictal periods and during subclinical epileptiform discharges. Some seizures showed obvious impairment, and others showed no change in driving performance. Seizures with driving impairment had significantly greater duration and were more likely to involve impaired consciousness than seizures without driving impairment. Seven of the seizures resulted in crashes. Seizures lasted an average of 75 seconds in patients who crashed, compared with an average of 30 seconds in patients who did not crash.
Driving simulations during inpatient video-EEG monitoring may be a useful way to determine factors that influence driving safety, the researchers concluded.
“It is going to take a lot more data to come up with a reliable way of predicting which people with epilepsy should drive and which should not,” said Dr. Blumenfeld. “We want to unearth more detail to learn if there are people with epilepsy who are driving who shouldn’t be, as well those who are not driving who can safely drive.”
HOUSTON—Seizure duration and impaired consciousness may be important factors that affect driving performance, according to a study presented at the 70th Annual Meeting of the American Epilepsy Society. “With further work, we hope to … determine whether specific seizure types or localizations present a greater driving risk, with the goal of providing improved guidance to physicians and patients with epilepsy,” researchers said.
A lack of data about driving performance during ictal and postictal periods can make it difficult for physicians to determine whether patients can safely drive.
To study driving impairment during seizures, Hal Blumenfeld, MD, PhD, Director of the Yale Clinical Neuroscience Imaging Center in New Haven, Connecticut, and colleagues asked patients to perform a driving simulation test during inpatient video EEG monitoring. Dr. Blumenfeld, the study’s lead author, is the Mark Loughridge and Michele Williams Professor of Neurology and a Professor of Neuroscience and Neurosurgery at Yale University.
The study included 20 patients who were observed in the epilepsy monitoring unit at Yale New Haven Hospital. Investigators analyzed ictal and interictal driving data captured prospectively from the driving simulator. A total of 33 seizures were analyzed. The investigators compared interictal and ictal driving performance through quantitative analysis. Variables included car velocity, steering wheel movement, braking, and crash occurrence.
Patients drove between one and 10 hours, with an average driving duration of about three hours. Patients had variable impairment during ictal and postictal periods and during subclinical epileptiform discharges. Some seizures showed obvious impairment, and others showed no change in driving performance. Seizures with driving impairment had significantly greater duration and were more likely to involve impaired consciousness than seizures without driving impairment. Seven of the seizures resulted in crashes. Seizures lasted an average of 75 seconds in patients who crashed, compared with an average of 30 seconds in patients who did not crash.
Driving simulations during inpatient video-EEG monitoring may be a useful way to determine factors that influence driving safety, the researchers concluded.
“It is going to take a lot more data to come up with a reliable way of predicting which people with epilepsy should drive and which should not,” said Dr. Blumenfeld. “We want to unearth more detail to learn if there are people with epilepsy who are driving who shouldn’t be, as well those who are not driving who can safely drive.”
What’s next for deep brain stimulation in OCD?
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again. 
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.