User login
The oncologist’s dilemma
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Neuropolitics in the age of extremism: Brain regions involved in hatred
We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.
We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.
But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.
Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.
This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.
Continued to: I think I sensed this odious scenario coming...
I think I sensed this odious scenario coming 2 years ago during the bizarre presidential election, when I wrote an editorial describing the “fear and loathing” that permeated the political process and the unusual behavior of the candidates.1 A year after the election, I commented about the toxic zeitgeist of political extremism from a psychiatric perspective.2 The situation appears to be getting worse, and the folie en masse is intensifying and its hateful cacophony is deafening to our sensibilities.
Aaron Beck, MD, the father of cognitive-behavioral therapy (CBT), wrote a book about hate.3 It may be a fantasy, but I wish the leaders on both sides would agree to a course of CBT to recognize the destructive path of intransigent hyper-partisanship. They might then transcend their egocentric attitudes and inspire millions of their followers to communicate rationally, instead of stoking the fires of resentment and enmity toward the “other side.”
Let’s get back to science: Where are the pathways of hate located in the brain? An interesting study was conducted to detect the neural circuits that mediate hate.4 The researchers obtained functional magnetic resonance imaging scans of participants while they were viewing the face of a person they hate compared with the face of an acquaintance toward whom they have neutral feelings. They also calculated a “hate score” for each participant for the analysis. They found that viewing a hated person increased the activity in several brain regions, including the medial frontal gyrus, right putamen, premotor cortex, frontal pole, and medial insula bilaterally. The activation in 3 areas correlated with the intensity of the hatred: right insula, right premotor cortex, and right frontal-medial gyrus. At the same time, the right superior frontal gyrus showed deactivation. Interestingly, hate and romantic love shared activation in 2 areas: the putamen and insula. This suggests that passionate love and passionate hate are 2 sides of the same neural coin! It prompts me to wonder what happens to the capacity to love among political extremists when their putamen and insula are filled up with hate. It also makes me wonder if unbridled hatred can be “enjoyable” and even addictive, as passionate romantic love is.
The bottom line: Consider the brain changes that are occurring on a large scale in at least a hundred million political partisans, and whether those neural circuits get even more intensely activated following the elections, regardless of the outcome.
Finally, we must remain cognizant of the epigenetic consequences of emotions and stress.5 There is solid scientific evidence that extremes of human experiences can modify gene expression in sperm and fetuses, resulting in a transgenerational effect upon the children of the extreme partisans, and also the children of nonpartisan observers, who experience unmitigated anxiety due to the inescapable cloud of negative affect shrouding their daily lives.6 So politicians should be cognizant that perpetuating a bitter war against each other may be detrimental to their progeny and future generations. I am frankly worried about the epigenetically disrupted emotional stability of voters circa 2035, born in these days of unprecedented and tumultuous hatred by their hyper-partisan parents.
Henry A. Nasrallah, MD
Editor-in-Chief
1. Nasrallah HA. Fear and loathing abound in the ‘off-label’ presidential election of 2016. Current Psychiatry. 2016;15(7):21,26.
2. Nasrallah HA. The toxic zeitgeist of hyper-partisanship: a psychiatric perspective. Current Psychiatry. 2018;17(2):17-18.
3. Beck AT. Prisoners of hate: the cognitive basis of anger, hostility, and violence. New York, NY: Harper-Collins; 1999.
4. Zeki S, Romaya JP. Neural correlates of hate. PloS One. 2008;3(10):e3556. doi: 10.1371/journal.pone.0003556.
5. Griffiths BB, Hunter RG. Neuroepigenetics of stress. Neuroscience. 2014;275:420-435.
6. Bartlett AA, Singh R, Hunter RG. Anxiety and epigenetics. Adv Exp Med Biol.2017;978:145-166.
We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.
We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.
But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.
Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.
This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.
Continued to: I think I sensed this odious scenario coming...
I think I sensed this odious scenario coming 2 years ago during the bizarre presidential election, when I wrote an editorial describing the “fear and loathing” that permeated the political process and the unusual behavior of the candidates.1 A year after the election, I commented about the toxic zeitgeist of political extremism from a psychiatric perspective.2 The situation appears to be getting worse, and the folie en masse is intensifying and its hateful cacophony is deafening to our sensibilities.
Aaron Beck, MD, the father of cognitive-behavioral therapy (CBT), wrote a book about hate.3 It may be a fantasy, but I wish the leaders on both sides would agree to a course of CBT to recognize the destructive path of intransigent hyper-partisanship. They might then transcend their egocentric attitudes and inspire millions of their followers to communicate rationally, instead of stoking the fires of resentment and enmity toward the “other side.”
Let’s get back to science: Where are the pathways of hate located in the brain? An interesting study was conducted to detect the neural circuits that mediate hate.4 The researchers obtained functional magnetic resonance imaging scans of participants while they were viewing the face of a person they hate compared with the face of an acquaintance toward whom they have neutral feelings. They also calculated a “hate score” for each participant for the analysis. They found that viewing a hated person increased the activity in several brain regions, including the medial frontal gyrus, right putamen, premotor cortex, frontal pole, and medial insula bilaterally. The activation in 3 areas correlated with the intensity of the hatred: right insula, right premotor cortex, and right frontal-medial gyrus. At the same time, the right superior frontal gyrus showed deactivation. Interestingly, hate and romantic love shared activation in 2 areas: the putamen and insula. This suggests that passionate love and passionate hate are 2 sides of the same neural coin! It prompts me to wonder what happens to the capacity to love among political extremists when their putamen and insula are filled up with hate. It also makes me wonder if unbridled hatred can be “enjoyable” and even addictive, as passionate romantic love is.
The bottom line: Consider the brain changes that are occurring on a large scale in at least a hundred million political partisans, and whether those neural circuits get even more intensely activated following the elections, regardless of the outcome.
Finally, we must remain cognizant of the epigenetic consequences of emotions and stress.5 There is solid scientific evidence that extremes of human experiences can modify gene expression in sperm and fetuses, resulting in a transgenerational effect upon the children of the extreme partisans, and also the children of nonpartisan observers, who experience unmitigated anxiety due to the inescapable cloud of negative affect shrouding their daily lives.6 So politicians should be cognizant that perpetuating a bitter war against each other may be detrimental to their progeny and future generations. I am frankly worried about the epigenetically disrupted emotional stability of voters circa 2035, born in these days of unprecedented and tumultuous hatred by their hyper-partisan parents.
Henry A. Nasrallah, MD
Editor-in-Chief
We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.
We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.
But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.
Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.
This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.
Continued to: I think I sensed this odious scenario coming...
I think I sensed this odious scenario coming 2 years ago during the bizarre presidential election, when I wrote an editorial describing the “fear and loathing” that permeated the political process and the unusual behavior of the candidates.1 A year after the election, I commented about the toxic zeitgeist of political extremism from a psychiatric perspective.2 The situation appears to be getting worse, and the folie en masse is intensifying and its hateful cacophony is deafening to our sensibilities.
Aaron Beck, MD, the father of cognitive-behavioral therapy (CBT), wrote a book about hate.3 It may be a fantasy, but I wish the leaders on both sides would agree to a course of CBT to recognize the destructive path of intransigent hyper-partisanship. They might then transcend their egocentric attitudes and inspire millions of their followers to communicate rationally, instead of stoking the fires of resentment and enmity toward the “other side.”
Let’s get back to science: Where are the pathways of hate located in the brain? An interesting study was conducted to detect the neural circuits that mediate hate.4 The researchers obtained functional magnetic resonance imaging scans of participants while they were viewing the face of a person they hate compared with the face of an acquaintance toward whom they have neutral feelings. They also calculated a “hate score” for each participant for the analysis. They found that viewing a hated person increased the activity in several brain regions, including the medial frontal gyrus, right putamen, premotor cortex, frontal pole, and medial insula bilaterally. The activation in 3 areas correlated with the intensity of the hatred: right insula, right premotor cortex, and right frontal-medial gyrus. At the same time, the right superior frontal gyrus showed deactivation. Interestingly, hate and romantic love shared activation in 2 areas: the putamen and insula. This suggests that passionate love and passionate hate are 2 sides of the same neural coin! It prompts me to wonder what happens to the capacity to love among political extremists when their putamen and insula are filled up with hate. It also makes me wonder if unbridled hatred can be “enjoyable” and even addictive, as passionate romantic love is.
The bottom line: Consider the brain changes that are occurring on a large scale in at least a hundred million political partisans, and whether those neural circuits get even more intensely activated following the elections, regardless of the outcome.
Finally, we must remain cognizant of the epigenetic consequences of emotions and stress.5 There is solid scientific evidence that extremes of human experiences can modify gene expression in sperm and fetuses, resulting in a transgenerational effect upon the children of the extreme partisans, and also the children of nonpartisan observers, who experience unmitigated anxiety due to the inescapable cloud of negative affect shrouding their daily lives.6 So politicians should be cognizant that perpetuating a bitter war against each other may be detrimental to their progeny and future generations. I am frankly worried about the epigenetically disrupted emotional stability of voters circa 2035, born in these days of unprecedented and tumultuous hatred by their hyper-partisan parents.
Henry A. Nasrallah, MD
Editor-in-Chief
1. Nasrallah HA. Fear and loathing abound in the ‘off-label’ presidential election of 2016. Current Psychiatry. 2016;15(7):21,26.
2. Nasrallah HA. The toxic zeitgeist of hyper-partisanship: a psychiatric perspective. Current Psychiatry. 2018;17(2):17-18.
3. Beck AT. Prisoners of hate: the cognitive basis of anger, hostility, and violence. New York, NY: Harper-Collins; 1999.
4. Zeki S, Romaya JP. Neural correlates of hate. PloS One. 2008;3(10):e3556. doi: 10.1371/journal.pone.0003556.
5. Griffiths BB, Hunter RG. Neuroepigenetics of stress. Neuroscience. 2014;275:420-435.
6. Bartlett AA, Singh R, Hunter RG. Anxiety and epigenetics. Adv Exp Med Biol.2017;978:145-166.
1. Nasrallah HA. Fear and loathing abound in the ‘off-label’ presidential election of 2016. Current Psychiatry. 2016;15(7):21,26.
2. Nasrallah HA. The toxic zeitgeist of hyper-partisanship: a psychiatric perspective. Current Psychiatry. 2018;17(2):17-18.
3. Beck AT. Prisoners of hate: the cognitive basis of anger, hostility, and violence. New York, NY: Harper-Collins; 1999.
4. Zeki S, Romaya JP. Neural correlates of hate. PloS One. 2008;3(10):e3556. doi: 10.1371/journal.pone.0003556.
5. Griffiths BB, Hunter RG. Neuroepigenetics of stress. Neuroscience. 2014;275:420-435.
6. Bartlett AA, Singh R, Hunter RG. Anxiety and epigenetics. Adv Exp Med Biol.2017;978:145-166.
Preventing brain damage in psychosis
I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor,
Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center
Clinical Assistant Professor of Psychiatry
Rosalind Franklin University
Chicago, Illinois
Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.
Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland
Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.
Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.
Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.3 Clemastine reverses acute leukoencephalopathy.4
If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.
The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.
Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico
References
1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.
Continue to: Dr. Nasrallah responds
Dr. Nasrallah responds
Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.
To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.
Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.
To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.
As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.1 This is also true for bipolar disorder recurrences.2 A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.3 Another 7-year study showed the same thing.4 It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.
To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”5 in which I mentioned all the above. I also pointed out the many neuroprotective effects of atypical antipsychotics in another editorial.6 Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.
Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri
References
1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the maligna
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuroprotection. Current Psychiatry. 2015;14(2):19-21.
I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor,
Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center
Clinical Assistant Professor of Psychiatry
Rosalind Franklin University
Chicago, Illinois
Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.
Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland
Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.
Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.
Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.3 Clemastine reverses acute leukoencephalopathy.4
If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.
The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.
Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico
References
1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.
Continue to: Dr. Nasrallah responds
Dr. Nasrallah responds
Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.
To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.
Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.
To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.
As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.1 This is also true for bipolar disorder recurrences.2 A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.3 Another 7-year study showed the same thing.4 It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.
To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”5 in which I mentioned all the above. I also pointed out the many neuroprotective effects of atypical antipsychotics in another editorial.6 Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.
Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri
References
1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the maligna
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuroprotection. Current Psychiatry. 2015;14(2):19-21.
I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor,
Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center
Clinical Assistant Professor of Psychiatry
Rosalind Franklin University
Chicago, Illinois
Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.
Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland
Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.
Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.
Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.3 Clemastine reverses acute leukoencephalopathy.4
If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.
The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.
Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico
References
1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.
Continue to: Dr. Nasrallah responds
Dr. Nasrallah responds
Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.
To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.
Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.
To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.
As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.1 This is also true for bipolar disorder recurrences.2 A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.3 Another 7-year study showed the same thing.4 It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.
To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”5 in which I mentioned all the above. I also pointed out the many neuroprotective effects of atypical antipsychotics in another editorial.6 Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.
Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri
References
1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the maligna
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuroprotection. Current Psychiatry. 2015;14(2):19-21.
Pregnancy registries are a valuable resource
Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of the human pregnancy experience. However, although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.
The strengths of these registries are their prospective nature (enrolled before the outcome is known) and enrollment over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions). Registries can identify early signals of teratogenicity, but they have several limitations: selection bias that results from voluntary reporting; target populations that are not representative; lost-to-follow-up pregnancies that may have had different outcomes than those with documented outcomes; elective terminations and fetal deaths without birth defects and spontaneous abortions, all of which may lack details; the lack of control groups (with some exceptions); and the publication of results that may be delayed or not be in a peer-reviewed journal. Because the total number of exposed pregnancies is unknown, the data cannot be used to calculate prevalences, but they can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports (reported after outcome is known). Such reports are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. But they may be helpful in detecting unusual patterns of birth defects.
For the following drugs, web addresses can be obtained from the Food and Drug Administration website, List of Pregnancy Exposure Registries.
MotherToBaby
A large registry, the MotherToBaby Organization of Teratology Information Specialists (OTIS) (877-311-8972), involves patients in several different categories and the effects of the drugs on the embryo-fetus: autoimmune diseases (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma at less than 20 weeks’ gestation; vaccines; and heterozygous or homozygous familial hypercholesterolemia.
For the autoimmune diseases, the drugs and trade names are abatacept (Orencia), adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade), leflunomide (Arava), otezla (Apremilast), teriflunomide (Aubagio), tocilizumab (Actemra), tofacitinib (Xeljanz), and ustekinumab (Stelara).
For the asthma group, the drug being investigated is mepolizumab (Nucala).
Two vaccines – for tetanus, diphtheria, and pertussis (Tdap) and meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menveo) – are being studied.
The last category is heterozygous or homozygous familial hypercholesterolemia. The two agents in this category are alirocumab (Praluent) and evolocumab (Repatha).
Other registries
Breast cancer
The Mother Pregnancy Registry, INC Research (800-690-6720), is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), or trastuzumab (Herceptin).
Epilepsy
The Antiepileptic Drug Pregnancy registry (888-233-2334) is studying eslicarbazepine (Aptiom) and pregabalin (Lyrica).
Fabry disease
The Fabry Registry, Genzyme Corp (617-591-5500) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.
Fibromyalgia
The Savella Pregnancy Registry (877-643-3010) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).
Hepatitis B
The Ribavirin Pregnancy Registry, INC Research (800-593-2214) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).
Hypercholesterolemia
Lomitapide (Juxtapid) is being studied by the Global Lomitapide Pregnancy Exposure Registry managed by Aegerion (877-902-4099). The drug is used for homozygous familial hypercholesterolemia.
Mucopolysaccharidosis
The Mucopolysaccharidosis I (MPS I) registry, Genzyme (617-591-5500) is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.
The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI), clinical surveillance program (BioMarin Pharmaceutical) (415-506-6849 or 415-506-6703).
Multiple sclerosis
Novartis is conducting the Gilenya Pregnancy Registry (877-598-7237) for patients with multiple sclerosis who are taking fingolimod (Gilenya).
Alemtuzumab (Lemtrada), also indicated for multiple sclerosis, is the target agent for the LEMTRADA Pregnancy Exposure Registry (866-758-2990).
Narcolepsy and other sleep disorders
Armodafinil (Nuvigil), used for excessive sleepiness associated with narcolepsy and other sleep disorders, is being studied in the Nuvigil Pregnancy Registry (866-404-4106). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry.
Osteoporosis
Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).
Others
Two Merck pregnancy registries (800-986-8999) cover the following conditions: type 2 diabetes sitagliptin+metformin (Janumet) or sitagliptin (Januvia); and migraine headaches rizatriptan (Maxalt).
GlaxoSmithKline is conducting two registries: the Belimumab Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (Benlysta) (877-681-6296); and Promacta Pregnancy Registry for women treated for thrombocytopenia with eltrombopag (Promacta) (888-825-5249).
Psychiatric Drugs
The National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) is studying 10 drugs: aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril), iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).
The National Pregnancy Registry for Antidepressants (844-405-6185) is studying amitriptyline (Elavil), amoxapine (Asendin), bupropion (Forfivo XL and Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), desvenlafaxine (Prisiq), doxepin (Sinequan), escitalopram (Lexapro), fluvoxamine (Luvox), fluoxetine (Prozac), imipramine (Tofranil), isocarboxazid (Marplan), levomilnacipran (Fetzima), maprotiline (Ludiomil), mirtazapine (Remeron), nefazodone (Serzone), nortriptyline (Pamelor), paroxetine (Paxil), phenelzine (Nardill), protriptyline (Vivactil), selegiline (Emsam), sertraline (Zoloft), tranylcypromine (Pamate), trazodone (Desyrel), trimipramine (Surmontil), venlafaxine (Effexor), and vilazodone (Viibryd).
The National Pregnancy Registry of Psychostimulants (866-961-2388) is studying amphetamine (Adderall), dextroamphetamine (Dexedrine and Focalin), lisdexamfetamine (Vyvanse), methylphenidate (Concerta, Daytrana, Desoxyn, Ritalin), and modafinil (Provigil).
The antidepressant duloxetine (Cymbalta) is being studied by the Cymbalta Pregnancy Registry (866-814-6975).
Transplant patients
Renal transplant patients exposed to mycophenolate (CellCept) can be enrolled in the Transplantation Pregnancy Registry International (877-955-6877) or the Mycophenolate Pregnancy Registry (800-617-8191). The Transplantation Pregnancy Registry International also is enrolling renal transplant patients exposed to belatacept (Nulojix).
Vaccines
A quadrivalent influenza vaccine (Afluria) is being studied by the Seqirus Influenza Vaccine Pregnancy Registry (855-358-8972). A second vaccine for meningococcal disease meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menactra) is under study by the Menactra Vaccine Pregnancy Registry (800-822-2463). The Bexsero Pregnancy Registry (877-413-4759) is open to patients who have received the meningococcal group B vaccine (Bexsero). The Hepatitis B Vaccine [Recombinant] Adjuvanted Pregnancy Registry, also listed as HEPLISAV-B, is enrolling patients who have received that vaccine (844-443-7734); it is supported by the Dynavax Technologies Corporation.
Because the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of the human pregnancy experience. However, although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.
The strengths of these registries are their prospective nature (enrolled before the outcome is known) and enrollment over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions). Registries can identify early signals of teratogenicity, but they have several limitations: selection bias that results from voluntary reporting; target populations that are not representative; lost-to-follow-up pregnancies that may have had different outcomes than those with documented outcomes; elective terminations and fetal deaths without birth defects and spontaneous abortions, all of which may lack details; the lack of control groups (with some exceptions); and the publication of results that may be delayed or not be in a peer-reviewed journal. Because the total number of exposed pregnancies is unknown, the data cannot be used to calculate prevalences, but they can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports (reported after outcome is known). Such reports are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. But they may be helpful in detecting unusual patterns of birth defects.
For the following drugs, web addresses can be obtained from the Food and Drug Administration website, List of Pregnancy Exposure Registries.
MotherToBaby
A large registry, the MotherToBaby Organization of Teratology Information Specialists (OTIS) (877-311-8972), involves patients in several different categories and the effects of the drugs on the embryo-fetus: autoimmune diseases (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma at less than 20 weeks’ gestation; vaccines; and heterozygous or homozygous familial hypercholesterolemia.
For the autoimmune diseases, the drugs and trade names are abatacept (Orencia), adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade), leflunomide (Arava), otezla (Apremilast), teriflunomide (Aubagio), tocilizumab (Actemra), tofacitinib (Xeljanz), and ustekinumab (Stelara).
For the asthma group, the drug being investigated is mepolizumab (Nucala).
Two vaccines – for tetanus, diphtheria, and pertussis (Tdap) and meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menveo) – are being studied.
The last category is heterozygous or homozygous familial hypercholesterolemia. The two agents in this category are alirocumab (Praluent) and evolocumab (Repatha).
Other registries
Breast cancer
The Mother Pregnancy Registry, INC Research (800-690-6720), is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), or trastuzumab (Herceptin).
Epilepsy
The Antiepileptic Drug Pregnancy registry (888-233-2334) is studying eslicarbazepine (Aptiom) and pregabalin (Lyrica).
Fabry disease
The Fabry Registry, Genzyme Corp (617-591-5500) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.
Fibromyalgia
The Savella Pregnancy Registry (877-643-3010) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).
Hepatitis B
The Ribavirin Pregnancy Registry, INC Research (800-593-2214) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).
Hypercholesterolemia
Lomitapide (Juxtapid) is being studied by the Global Lomitapide Pregnancy Exposure Registry managed by Aegerion (877-902-4099). The drug is used for homozygous familial hypercholesterolemia.
Mucopolysaccharidosis
The Mucopolysaccharidosis I (MPS I) registry, Genzyme (617-591-5500) is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.
The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI), clinical surveillance program (BioMarin Pharmaceutical) (415-506-6849 or 415-506-6703).
Multiple sclerosis
Novartis is conducting the Gilenya Pregnancy Registry (877-598-7237) for patients with multiple sclerosis who are taking fingolimod (Gilenya).
Alemtuzumab (Lemtrada), also indicated for multiple sclerosis, is the target agent for the LEMTRADA Pregnancy Exposure Registry (866-758-2990).
Narcolepsy and other sleep disorders
Armodafinil (Nuvigil), used for excessive sleepiness associated with narcolepsy and other sleep disorders, is being studied in the Nuvigil Pregnancy Registry (866-404-4106). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry.
Osteoporosis
Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).
Others
Two Merck pregnancy registries (800-986-8999) cover the following conditions: type 2 diabetes sitagliptin+metformin (Janumet) or sitagliptin (Januvia); and migraine headaches rizatriptan (Maxalt).
GlaxoSmithKline is conducting two registries: the Belimumab Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (Benlysta) (877-681-6296); and Promacta Pregnancy Registry for women treated for thrombocytopenia with eltrombopag (Promacta) (888-825-5249).
Psychiatric Drugs
The National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) is studying 10 drugs: aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril), iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).
The National Pregnancy Registry for Antidepressants (844-405-6185) is studying amitriptyline (Elavil), amoxapine (Asendin), bupropion (Forfivo XL and Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), desvenlafaxine (Prisiq), doxepin (Sinequan), escitalopram (Lexapro), fluvoxamine (Luvox), fluoxetine (Prozac), imipramine (Tofranil), isocarboxazid (Marplan), levomilnacipran (Fetzima), maprotiline (Ludiomil), mirtazapine (Remeron), nefazodone (Serzone), nortriptyline (Pamelor), paroxetine (Paxil), phenelzine (Nardill), protriptyline (Vivactil), selegiline (Emsam), sertraline (Zoloft), tranylcypromine (Pamate), trazodone (Desyrel), trimipramine (Surmontil), venlafaxine (Effexor), and vilazodone (Viibryd).
The National Pregnancy Registry of Psychostimulants (866-961-2388) is studying amphetamine (Adderall), dextroamphetamine (Dexedrine and Focalin), lisdexamfetamine (Vyvanse), methylphenidate (Concerta, Daytrana, Desoxyn, Ritalin), and modafinil (Provigil).
The antidepressant duloxetine (Cymbalta) is being studied by the Cymbalta Pregnancy Registry (866-814-6975).
Transplant patients
Renal transplant patients exposed to mycophenolate (CellCept) can be enrolled in the Transplantation Pregnancy Registry International (877-955-6877) or the Mycophenolate Pregnancy Registry (800-617-8191). The Transplantation Pregnancy Registry International also is enrolling renal transplant patients exposed to belatacept (Nulojix).
Vaccines
A quadrivalent influenza vaccine (Afluria) is being studied by the Seqirus Influenza Vaccine Pregnancy Registry (855-358-8972). A second vaccine for meningococcal disease meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menactra) is under study by the Menactra Vaccine Pregnancy Registry (800-822-2463). The Bexsero Pregnancy Registry (877-413-4759) is open to patients who have received the meningococcal group B vaccine (Bexsero). The Hepatitis B Vaccine [Recombinant] Adjuvanted Pregnancy Registry, also listed as HEPLISAV-B, is enrolling patients who have received that vaccine (844-443-7734); it is supported by the Dynavax Technologies Corporation.
Because the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of the human pregnancy experience. However, although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.
The strengths of these registries are their prospective nature (enrolled before the outcome is known) and enrollment over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions). Registries can identify early signals of teratogenicity, but they have several limitations: selection bias that results from voluntary reporting; target populations that are not representative; lost-to-follow-up pregnancies that may have had different outcomes than those with documented outcomes; elective terminations and fetal deaths without birth defects and spontaneous abortions, all of which may lack details; the lack of control groups (with some exceptions); and the publication of results that may be delayed or not be in a peer-reviewed journal. Because the total number of exposed pregnancies is unknown, the data cannot be used to calculate prevalences, but they can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports (reported after outcome is known). Such reports are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. But they may be helpful in detecting unusual patterns of birth defects.
For the following drugs, web addresses can be obtained from the Food and Drug Administration website, List of Pregnancy Exposure Registries.
MotherToBaby
A large registry, the MotherToBaby Organization of Teratology Information Specialists (OTIS) (877-311-8972), involves patients in several different categories and the effects of the drugs on the embryo-fetus: autoimmune diseases (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma at less than 20 weeks’ gestation; vaccines; and heterozygous or homozygous familial hypercholesterolemia.
For the autoimmune diseases, the drugs and trade names are abatacept (Orencia), adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade), leflunomide (Arava), otezla (Apremilast), teriflunomide (Aubagio), tocilizumab (Actemra), tofacitinib (Xeljanz), and ustekinumab (Stelara).
For the asthma group, the drug being investigated is mepolizumab (Nucala).
Two vaccines – for tetanus, diphtheria, and pertussis (Tdap) and meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menveo) – are being studied.
The last category is heterozygous or homozygous familial hypercholesterolemia. The two agents in this category are alirocumab (Praluent) and evolocumab (Repatha).
Other registries
Breast cancer
The Mother Pregnancy Registry, INC Research (800-690-6720), is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), or trastuzumab (Herceptin).
Epilepsy
The Antiepileptic Drug Pregnancy registry (888-233-2334) is studying eslicarbazepine (Aptiom) and pregabalin (Lyrica).
Fabry disease
The Fabry Registry, Genzyme Corp (617-591-5500) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.
Fibromyalgia
The Savella Pregnancy Registry (877-643-3010) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).
Hepatitis B
The Ribavirin Pregnancy Registry, INC Research (800-593-2214) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).
Hypercholesterolemia
Lomitapide (Juxtapid) is being studied by the Global Lomitapide Pregnancy Exposure Registry managed by Aegerion (877-902-4099). The drug is used for homozygous familial hypercholesterolemia.
Mucopolysaccharidosis
The Mucopolysaccharidosis I (MPS I) registry, Genzyme (617-591-5500) is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.
The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI), clinical surveillance program (BioMarin Pharmaceutical) (415-506-6849 or 415-506-6703).
Multiple sclerosis
Novartis is conducting the Gilenya Pregnancy Registry (877-598-7237) for patients with multiple sclerosis who are taking fingolimod (Gilenya).
Alemtuzumab (Lemtrada), also indicated for multiple sclerosis, is the target agent for the LEMTRADA Pregnancy Exposure Registry (866-758-2990).
Narcolepsy and other sleep disorders
Armodafinil (Nuvigil), used for excessive sleepiness associated with narcolepsy and other sleep disorders, is being studied in the Nuvigil Pregnancy Registry (866-404-4106). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry.
Osteoporosis
Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).
Others
Two Merck pregnancy registries (800-986-8999) cover the following conditions: type 2 diabetes sitagliptin+metformin (Janumet) or sitagliptin (Januvia); and migraine headaches rizatriptan (Maxalt).
GlaxoSmithKline is conducting two registries: the Belimumab Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (Benlysta) (877-681-6296); and Promacta Pregnancy Registry for women treated for thrombocytopenia with eltrombopag (Promacta) (888-825-5249).
Psychiatric Drugs
The National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) is studying 10 drugs: aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril), iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).
The National Pregnancy Registry for Antidepressants (844-405-6185) is studying amitriptyline (Elavil), amoxapine (Asendin), bupropion (Forfivo XL and Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), desvenlafaxine (Prisiq), doxepin (Sinequan), escitalopram (Lexapro), fluvoxamine (Luvox), fluoxetine (Prozac), imipramine (Tofranil), isocarboxazid (Marplan), levomilnacipran (Fetzima), maprotiline (Ludiomil), mirtazapine (Remeron), nefazodone (Serzone), nortriptyline (Pamelor), paroxetine (Paxil), phenelzine (Nardill), protriptyline (Vivactil), selegiline (Emsam), sertraline (Zoloft), tranylcypromine (Pamate), trazodone (Desyrel), trimipramine (Surmontil), venlafaxine (Effexor), and vilazodone (Viibryd).
The National Pregnancy Registry of Psychostimulants (866-961-2388) is studying amphetamine (Adderall), dextroamphetamine (Dexedrine and Focalin), lisdexamfetamine (Vyvanse), methylphenidate (Concerta, Daytrana, Desoxyn, Ritalin), and modafinil (Provigil).
The antidepressant duloxetine (Cymbalta) is being studied by the Cymbalta Pregnancy Registry (866-814-6975).
Transplant patients
Renal transplant patients exposed to mycophenolate (CellCept) can be enrolled in the Transplantation Pregnancy Registry International (877-955-6877) or the Mycophenolate Pregnancy Registry (800-617-8191). The Transplantation Pregnancy Registry International also is enrolling renal transplant patients exposed to belatacept (Nulojix).
Vaccines
A quadrivalent influenza vaccine (Afluria) is being studied by the Seqirus Influenza Vaccine Pregnancy Registry (855-358-8972). A second vaccine for meningococcal disease meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 (Menactra) is under study by the Menactra Vaccine Pregnancy Registry (800-822-2463). The Bexsero Pregnancy Registry (877-413-4759) is open to patients who have received the meningococcal group B vaccine (Bexsero). The Hepatitis B Vaccine [Recombinant] Adjuvanted Pregnancy Registry, also listed as HEPLISAV-B, is enrolling patients who have received that vaccine (844-443-7734); it is supported by the Dynavax Technologies Corporation.
Because the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
Full disclosure
I have nothing to disclose.
That is the first line on my second slide in just about every talk I give. I have no financial conflicts of interest. I no longer accept meals from pharmaceutical companies, I no longer conduct pharmaceutical company sponsored research, and I no longer give talks that include honoraria from pharmaceutical companies. I turn down payments from pharmaceutical companies when I participate in drug-monitoring safety boards and advisory committees. I do not have a financial conflict of interest.
Or do I?
In preparing to write this essay, I searched the Open Payments website (www.cms.gov/OpenPayments/index.html) for my name. Open Payments is the product of the Physician Payments Sunshine Act passed in 2010 as part of the Affordable Care Act. The website went live in September 2014 with the intention of making public all payments made to physicians from device and drug makers. I was happy to confirm that I have received no “General Payments,” which are payments for meals, travel, honoraria, consulting, and the like. However, I was surprised to learn that I did receive “Associated Research” payments. According to the website, an Associated Research payment is “funding for a research project or study where the physician is named as a principal investigator.”
I still have a few trials open under my name, but none have accrued a patient in more than 7 years. Nonetheless, I am on record, and publicly so, for accepting an Associated payment for research to the tune of $1,308,360.06.
Upon learning this, my thoughts turned to the New York Times. The Times recently published an expose in cooperation with ProPublica. In it, a prominent cancer researcher at Memorial Sloan Kettering was accused of repeatedly failing to disclose his substantial financial conflicts of interest. The payments creating the conflict were listed on the Open Payments website. Since financial disclosure is almost always required for a manuscript listed in PubMed, a simple comparison of two public websites provided the journalists with nearly all the information they needed to conclude malfeasance in disclosure.
In response, the accused admitted the failure to disclose, but attributed it to an unintentional error. In the frenzy that followed, a man of towering stature, a paragon of cancer research, submitted his resignation. The sequence of events was tragic. Had the payments been for research instead of services rendered would the consequences have been the same?
Most of us believe corporate payments for research are less likely to influence our prescribing and consulting habits than are general payments for entertainment and speaking engagements. I remember receiving my first research grant from the now defunct pharma company Immunex. It was for $10,000 – a paltry sum – but enough for me to set up a clinical trial using Immunex’s drugs. I was flattered, indebted, and conflicted from that point forward. Funded research propels our careers forward. Thinking research payments bias our decision making less than direct payments is naive. Money corrupts, and that is why research dollars need to be disclosed whenever we discuss research at the podium or in print.
With appropriate indignation, I explored the Open Payments website to learn more of my hitherto unknown payment. It was attached to a multicenter, randomized clinical trial for which I served as local principal investigator. The payment was made in January 2017 and our research team cannot verify such a payment was ever received. According to the website, the payment was not disputed. I sought to dispute it.
Our friends at the Centers for Medicare and Medicaid Services do not make filing a dispute easy. I first had to register with my home address and create a new password that, of course, needs to be changed every 60 days. I duly registered and logged into the website as instructed. I followed instructions and filled in data fields for about an additional 10 pages before being informed that I needed to logout, then log back in, to access the Open Payments application. When I did that, I was greeted with instructions to register in the Open Payments system. I then realized that all I had done to that point was register with the CMS.gov portal, not Open Payments. In for a dime, in for a dollar, I registered with Open Payments.
I almost gave up when they asked me to provide a Physician Taxonomy Code. It took me a long time to find it. For those interested, the code for Hematology is 207RH0000X. With that code entered in the right box, I was only two pages away from being registered and ready to open the dispute. Failure hit me like a lake effect snow storm. Despite my diligence, I was not “vetted” and could not file a dispute. I must have done something wrong and cannot seem to investigate the payment further, but I’m sure the New York Times could.
Now, I don’t know if I have anything to disclose or not. I do know that I have to investigate my payment the best I can, that I have to disclose it if it is real, and that I have to check Open Payments every so often to make sure I am not surprised by an investigative journalist’s report in the future. Add these to the pantheon of onerous requirements for a successful academic career.
Many wear their entanglements as a badge of honor on slides highlighting a long list of conflicts. One speaker joked that she had so many conflicts that she had no conflicts. Clearly, much like alarm fatigue, the constant display of financial conflict of interest disclosures rarely raises red flags in an audience of peers. To an audience of interested lay persons, though, those conflicts may be very important and relevant.
It is our duty to accurately account for and report them no matter the difficulty in doing so. Failure to do so can carry tragic consequences.
Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].
I have nothing to disclose.
That is the first line on my second slide in just about every talk I give. I have no financial conflicts of interest. I no longer accept meals from pharmaceutical companies, I no longer conduct pharmaceutical company sponsored research, and I no longer give talks that include honoraria from pharmaceutical companies. I turn down payments from pharmaceutical companies when I participate in drug-monitoring safety boards and advisory committees. I do not have a financial conflict of interest.
Or do I?
In preparing to write this essay, I searched the Open Payments website (www.cms.gov/OpenPayments/index.html) for my name. Open Payments is the product of the Physician Payments Sunshine Act passed in 2010 as part of the Affordable Care Act. The website went live in September 2014 with the intention of making public all payments made to physicians from device and drug makers. I was happy to confirm that I have received no “General Payments,” which are payments for meals, travel, honoraria, consulting, and the like. However, I was surprised to learn that I did receive “Associated Research” payments. According to the website, an Associated Research payment is “funding for a research project or study where the physician is named as a principal investigator.”
I still have a few trials open under my name, but none have accrued a patient in more than 7 years. Nonetheless, I am on record, and publicly so, for accepting an Associated payment for research to the tune of $1,308,360.06.
Upon learning this, my thoughts turned to the New York Times. The Times recently published an expose in cooperation with ProPublica. In it, a prominent cancer researcher at Memorial Sloan Kettering was accused of repeatedly failing to disclose his substantial financial conflicts of interest. The payments creating the conflict were listed on the Open Payments website. Since financial disclosure is almost always required for a manuscript listed in PubMed, a simple comparison of two public websites provided the journalists with nearly all the information they needed to conclude malfeasance in disclosure.
In response, the accused admitted the failure to disclose, but attributed it to an unintentional error. In the frenzy that followed, a man of towering stature, a paragon of cancer research, submitted his resignation. The sequence of events was tragic. Had the payments been for research instead of services rendered would the consequences have been the same?
Most of us believe corporate payments for research are less likely to influence our prescribing and consulting habits than are general payments for entertainment and speaking engagements. I remember receiving my first research grant from the now defunct pharma company Immunex. It was for $10,000 – a paltry sum – but enough for me to set up a clinical trial using Immunex’s drugs. I was flattered, indebted, and conflicted from that point forward. Funded research propels our careers forward. Thinking research payments bias our decision making less than direct payments is naive. Money corrupts, and that is why research dollars need to be disclosed whenever we discuss research at the podium or in print.
With appropriate indignation, I explored the Open Payments website to learn more of my hitherto unknown payment. It was attached to a multicenter, randomized clinical trial for which I served as local principal investigator. The payment was made in January 2017 and our research team cannot verify such a payment was ever received. According to the website, the payment was not disputed. I sought to dispute it.
Our friends at the Centers for Medicare and Medicaid Services do not make filing a dispute easy. I first had to register with my home address and create a new password that, of course, needs to be changed every 60 days. I duly registered and logged into the website as instructed. I followed instructions and filled in data fields for about an additional 10 pages before being informed that I needed to logout, then log back in, to access the Open Payments application. When I did that, I was greeted with instructions to register in the Open Payments system. I then realized that all I had done to that point was register with the CMS.gov portal, not Open Payments. In for a dime, in for a dollar, I registered with Open Payments.
I almost gave up when they asked me to provide a Physician Taxonomy Code. It took me a long time to find it. For those interested, the code for Hematology is 207RH0000X. With that code entered in the right box, I was only two pages away from being registered and ready to open the dispute. Failure hit me like a lake effect snow storm. Despite my diligence, I was not “vetted” and could not file a dispute. I must have done something wrong and cannot seem to investigate the payment further, but I’m sure the New York Times could.
Now, I don’t know if I have anything to disclose or not. I do know that I have to investigate my payment the best I can, that I have to disclose it if it is real, and that I have to check Open Payments every so often to make sure I am not surprised by an investigative journalist’s report in the future. Add these to the pantheon of onerous requirements for a successful academic career.
Many wear their entanglements as a badge of honor on slides highlighting a long list of conflicts. One speaker joked that she had so many conflicts that she had no conflicts. Clearly, much like alarm fatigue, the constant display of financial conflict of interest disclosures rarely raises red flags in an audience of peers. To an audience of interested lay persons, though, those conflicts may be very important and relevant.
It is our duty to accurately account for and report them no matter the difficulty in doing so. Failure to do so can carry tragic consequences.
Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].
I have nothing to disclose.
That is the first line on my second slide in just about every talk I give. I have no financial conflicts of interest. I no longer accept meals from pharmaceutical companies, I no longer conduct pharmaceutical company sponsored research, and I no longer give talks that include honoraria from pharmaceutical companies. I turn down payments from pharmaceutical companies when I participate in drug-monitoring safety boards and advisory committees. I do not have a financial conflict of interest.
Or do I?
In preparing to write this essay, I searched the Open Payments website (www.cms.gov/OpenPayments/index.html) for my name. Open Payments is the product of the Physician Payments Sunshine Act passed in 2010 as part of the Affordable Care Act. The website went live in September 2014 with the intention of making public all payments made to physicians from device and drug makers. I was happy to confirm that I have received no “General Payments,” which are payments for meals, travel, honoraria, consulting, and the like. However, I was surprised to learn that I did receive “Associated Research” payments. According to the website, an Associated Research payment is “funding for a research project or study where the physician is named as a principal investigator.”
I still have a few trials open under my name, but none have accrued a patient in more than 7 years. Nonetheless, I am on record, and publicly so, for accepting an Associated payment for research to the tune of $1,308,360.06.
Upon learning this, my thoughts turned to the New York Times. The Times recently published an expose in cooperation with ProPublica. In it, a prominent cancer researcher at Memorial Sloan Kettering was accused of repeatedly failing to disclose his substantial financial conflicts of interest. The payments creating the conflict were listed on the Open Payments website. Since financial disclosure is almost always required for a manuscript listed in PubMed, a simple comparison of two public websites provided the journalists with nearly all the information they needed to conclude malfeasance in disclosure.
In response, the accused admitted the failure to disclose, but attributed it to an unintentional error. In the frenzy that followed, a man of towering stature, a paragon of cancer research, submitted his resignation. The sequence of events was tragic. Had the payments been for research instead of services rendered would the consequences have been the same?
Most of us believe corporate payments for research are less likely to influence our prescribing and consulting habits than are general payments for entertainment and speaking engagements. I remember receiving my first research grant from the now defunct pharma company Immunex. It was for $10,000 – a paltry sum – but enough for me to set up a clinical trial using Immunex’s drugs. I was flattered, indebted, and conflicted from that point forward. Funded research propels our careers forward. Thinking research payments bias our decision making less than direct payments is naive. Money corrupts, and that is why research dollars need to be disclosed whenever we discuss research at the podium or in print.
With appropriate indignation, I explored the Open Payments website to learn more of my hitherto unknown payment. It was attached to a multicenter, randomized clinical trial for which I served as local principal investigator. The payment was made in January 2017 and our research team cannot verify such a payment was ever received. According to the website, the payment was not disputed. I sought to dispute it.
Our friends at the Centers for Medicare and Medicaid Services do not make filing a dispute easy. I first had to register with my home address and create a new password that, of course, needs to be changed every 60 days. I duly registered and logged into the website as instructed. I followed instructions and filled in data fields for about an additional 10 pages before being informed that I needed to logout, then log back in, to access the Open Payments application. When I did that, I was greeted with instructions to register in the Open Payments system. I then realized that all I had done to that point was register with the CMS.gov portal, not Open Payments. In for a dime, in for a dollar, I registered with Open Payments.
I almost gave up when they asked me to provide a Physician Taxonomy Code. It took me a long time to find it. For those interested, the code for Hematology is 207RH0000X. With that code entered in the right box, I was only two pages away from being registered and ready to open the dispute. Failure hit me like a lake effect snow storm. Despite my diligence, I was not “vetted” and could not file a dispute. I must have done something wrong and cannot seem to investigate the payment further, but I’m sure the New York Times could.
Now, I don’t know if I have anything to disclose or not. I do know that I have to investigate my payment the best I can, that I have to disclose it if it is real, and that I have to check Open Payments every so often to make sure I am not surprised by an investigative journalist’s report in the future. Add these to the pantheon of onerous requirements for a successful academic career.
Many wear their entanglements as a badge of honor on slides highlighting a long list of conflicts. One speaker joked that she had so many conflicts that she had no conflicts. Clearly, much like alarm fatigue, the constant display of financial conflict of interest disclosures rarely raises red flags in an audience of peers. To an audience of interested lay persons, though, those conflicts may be very important and relevant.
It is our duty to accurately account for and report them no matter the difficulty in doing so. Failure to do so can carry tragic consequences.
Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].
Vaginal intraepithelial neoplasia: What to do when dysplasia persists after hysterectomy
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
Vaginal intraepithelial neoplasia (VAIN) is a condition that frequently poses therapeutic dilemmas for gynecologists. VAIN represents dysplastic changes to the epithelium of the vaginal mucosa, and like cervical neoplasia, the extent of disease is characterized as levels I, II, or III dependent upon the depth of involvement in the epithelial layer by dysplastic cells. While VAIN itself typically is asymptomatic and not a harmful condition, it carries a 12% risk of progression to invasive vaginal carcinoma, so accurate identification, thorough treatment, and ongoing surveillance are essential.1
VAIN is associated with high-risk human papillomavirus (HPV) infection, tobacco use, and prior cervical dysplasia. Of women with VAIN, 65% have undergone a prior hysterectomy for cervical dysplasia, which emphasizes the nondefinitive nature of such an intervention.2 These women should be very closely followed for at least 20 years with vaginal cytologic and/or HPV surveillance. High-risk HPV infection is present in 85% of women with VAIN, and the presence of high-risk HPV is a predictor for recurrent VAIN. Recurrent and persistent VAIN also is more common in postmenopausal women and those with multifocal disease.
The most common location for VAIN is at the upper third of the vagina (including the vaginal cuff). It commonly arises within the vaginal fornices, which may be difficult to fully visualize because of their puckered appearance, redundant vaginal tissues, and extensive vaginal rogation.
A diagnosis of VAIN is typically obtained from vaginal cytology which reveals atypical or dysplastic cells. Such a result should prompt the physician to perform vaginal colposcopy and directed biopsies. Comprehensive visualization of the vaginal cuff can be limited in cases where the vaginal fornices are tethered, deeply puckered, or when there is significant mucosal rogation.
The application of 4% acetic acid or Lugol’s iodine are techniques that can enhance the detection of dysplastic vaginal mucosa. Lugol’s iodine selectively stains normal, glycogenated cells, and spares dysplastic glycogen-free cells. The sharp contrast between the brown iodine-stained tissues and the white dysplastic tissues aids in detection of dysplastic areas.
If colposcopic biopsy reveals low grade dysplasia (VAIN I) it does not require intervention, and has a very low rate of conversion to invasive vaginal carcinoma. However moderate- and high-grade vaginal dysplastic lesions should be treated because of the potential for malignant transformation.
Options for treatment of VAIN include topical, ablative, and excisional procedures. Observation also is an option but should be reserved for patients who are closely monitored with repeated colposcopic examinations, and probably should best be reserved for patients with VAIN I or II lesions.
Excisional procedures
The most common excisional procedure employed for VAIN is upper vaginectomy. In this procedure, the surgeon grasps and tents up the vaginal mucosa, incises the mucosa without penetrating the subepithelial tissue layers such as bladder and rectum. The vaginal mucosa then is carefully separated from the underlying endopelvic fascial plane. The specimen should be oriented, ideally on a cork board, with pins or sutures to ascribe margins and borders. Excision is best utilized for women with unifocal disease, or those who fail or do not tolerate ablative or topical interventions.
The most significant risks of excision include the potential for damage to underlying pelvic visceral structures, which is particularly concerning in postmenopausal women with thin vaginal epithelium. Vaginectomy is commonly associated with vaginal shortening or narrowing, which can be deleterious for quality of life. Retrospective series have described a 30% incidence of recurrence after vaginectomy, likely secondary to incomplete excision of all affected tissue.3
Ablation
Ablation of dysplastic foci with a carbon dioxide (CO2) laser is a common method for treatment of VAIN. CO2 laser should ablate tissue to a 1.5 mm minimum depth.3 The benefit of using CO2 laser is its ability to treat multifocal disease in situ without an extensive excisional procedure.
It is technically more straightforward than upper vaginectomy with less blood loss and shorter surgical times, and it can be easily accomplished in an outpatient surgical or office setting. However, one of its greatest limitations is the difficulty in visualizing all lesions and therefore adequately treating all sites. The vaginal rogations also make adequate laser ablation challenging because laser only is able to effectively ablate tissue that is oriented perpendicular to the laser beam.
In addition, there is no pathologic confirmation of adequacy of excision or margin status. These features may contribute to the modestly higher rates of recurrence of dysplasia following laser ablation, compared with vaginectomy.3 It also has been associated with more vaginal scarring than vaginectomy, which can have a negative effect on sexual health.
Topical agents
The most commonly utilized topical therapy for VAIN is the antimetabolite chemotherapeutic agent 5-fluorouracil (5FU). A typical schedule for 5FU treatment is to apply vaginally, at night, once a week for 8 weeks.4 Because it can cause extensive irritation to the vulvar and urethral epithelium, patients are recommended to apply barrier creams or ointments before and following the use of 5FU for several days, wash hands thoroughly after application, and to rinse and shower in the morning after rising. Severe irritation occurs in up to 16% of patients, but in general it is very well tolerated.
Its virtue is that it is able to conform and travel to all parts of the vaginal mucosa, including those that are poorly visualized within the fornices or vaginal folds. 5FU does not require a hospitalization or surgical procedure, can be applied by the patient at home, and preserves vaginal length and function. In recent reports, 5FU is associated with the lowest rates of recurrence (10%-30%), compared with excision or ablation, and therefore is a very attractive option for primary therapy.3 However, it requires patients to have a degree of comfort with vaginal application of drug and adherence with perineal care strategies to minimize the likelihood of toxicity.
The immune response modifier, imiquimod, that is commonly used in the treatment of vulvar dysplasia also has been described in the treatment of VAIN. It appears to have high rates of clearance (greater than 75%) and be most effective in the treatment of VAIN I.5 It requires application under colposcopic guidance three times a week for 8 weeks, which is a laborious undertaking for both patient and physician. Like 5FU, imiquimod is associated with vulvar and perineal irritation.
Vaginal estrogens are an alternative topical therapy for moderate- and high-grade VAIN and particularly useful for postmenopausal patients. They have been associated with a high rate (up to 90%) of resolution on follow-up vaginal cytology testing and are not associated with toxicities of the above stated therapies.6 Vaginal estrogen can be used alone or in addition to other therapeutic strategies. For example, it can be added to the nontreatment days of 5FU or postoperatively prescribed following laser or excisional procedures.
Radiation
Intracavitary brachytherapy is a technique in which a radiation source is placed within a cylinder or ovoids and placed within the vagina.7 Typically 45 Gy is delivered to a depth 0.5mm below the vaginal mucosal surface (“point z”). Recurrence occurs is approximately 10%-15% of patients, and toxicities can be severe, including vaginal stenosis and ulceration. This aggressive therapy typically is best reserved for cases that are refractory to other therapies. Following radiation, subsequent treatments are more difficult because of radiation-induced changes to the vaginal mucosa that can affect healing.
Vaginal dysplasia is a relatively common sequelae of high-risk HPV, particularly among women who have had a prior hysterectomy for cervical dysplasia. Because of anatomic changes following hysterectomy, adequate visualization and comprehensive vaginal treatment is difficult. Therefore, surgeons should avoid utilization of hysterectomy as a routine strategy to “cure” dysplasia as it may fail to achieve this cure and make subsequent evaluations and treatments of persistent dysplasia more difficult. Women who have had a hysterectomy for dysplasia should be closely followed for several decades, and they should be counseled that they have a persistent risk for vaginal disease. When VAIN develops, clinicians should consider topical therapies as primary treatment options because they may minimize toxicity and have high rates of enduring response.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant conflicts of interest.
References
1. Gynecol Oncol. 2016 Jun;141(3):507-10.
2. Arch Gynecol Obstet. 2016 Feb;293(2):415-9.
3. Anticancer Res. 2013 Jan;33(1):29-38.
4. Obstet Gynecol. 2017 Dec;130(6):1237-43.
5. Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:129-36.
6. J Low Genit Tract Dis. 2014 Apr;18(2):115-21.
7. Gynecol Oncol. 2007 Jul;106(1):105-11.
Johnson v. Monsanto: Roundup and product liability
QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.
Which of the following statements is incorrect?
A. These are all examples of product liability.
B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.
C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.
D. It is now harder to include multiple plaintiffs in a class-action lawsuit.
E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.
ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.1 DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.
The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”2 Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.
At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.
Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.
The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.
Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.
In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.3 He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.
The California Supreme Court went beyond the law of contracts and negligence by introducing the notion of strict liability, which centers on whether a product is defective and unreasonably dangerous. It holds that a professional supplier who sells a product that is both defective and unreasonably dangerous is strictly liable to foreseeable plaintiffs.
“Defective” is usually defined as product quality that is less than what a reasonable consumer expects. It can be a design, manufacturing, or marketing defect, the latter instance typically showing up as a failure to warn. “Unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Product liability lawsuits commonly involve pharmaceutical products and medical devices. Recent examples are suits against Pfizer over Lipitor’s alleged role as a cause of diabetes and against Johnson & Johnson over its talcum products purportedly causing ovarian cancer.4
When the same product injures multiple plaintiffs, they may band together to file a common legal action against the manufacturer. This is called a class-action suit, and will proceed if it is certified to satisfy four prerequisites: numerosity, commonality, typicality, and adequacy.5 A class-action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
A recent U.S. Supreme Court decision has, however, put a damper on class-action suits by tightening the jurisdictional requirement.6
The case involved Bristol-Myers Squibb, which was sued in California by several hundred individuals from 33 states for injuries from the platelet inhibitor Plavix (clopidogrel). The issue was whether non–California residents could sue in that state for injuries incurred elsewhere.
In a 8-1 decision, the U.S. Supreme Court held that California courts did not have specific jurisdiction to hear the claims of nonresidents without identifying an adequate link between the state and the nonresidents’ claims, as they weren’t prescribed Plavix in the state, didn’t buy or take the drug there, and weren’t injured by the drug there.
Finally, note that, should a doctor fail to warn an injured patient of a known medication risk, the patient may have a claim against the doctor – but usually not against the drug manufacturer. This is termed the “learned-intermediary doctrine.” The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through its sales reps and in its package insert and the Physician’s Desk Reference. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship.
Such lawsuits fall in the common category of medical negligence and lack of informed consent, and are not considered a product liability action.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.
2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.
3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).
4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.
5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.
6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).
QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.
Which of the following statements is incorrect?
A. These are all examples of product liability.
B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.
C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.
D. It is now harder to include multiple plaintiffs in a class-action lawsuit.
E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.
ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.1 DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.
The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”2 Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.
At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.
Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.
The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.
Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.
In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.3 He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.
The California Supreme Court went beyond the law of contracts and negligence by introducing the notion of strict liability, which centers on whether a product is defective and unreasonably dangerous. It holds that a professional supplier who sells a product that is both defective and unreasonably dangerous is strictly liable to foreseeable plaintiffs.
“Defective” is usually defined as product quality that is less than what a reasonable consumer expects. It can be a design, manufacturing, or marketing defect, the latter instance typically showing up as a failure to warn. “Unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Product liability lawsuits commonly involve pharmaceutical products and medical devices. Recent examples are suits against Pfizer over Lipitor’s alleged role as a cause of diabetes and against Johnson & Johnson over its talcum products purportedly causing ovarian cancer.4
When the same product injures multiple plaintiffs, they may band together to file a common legal action against the manufacturer. This is called a class-action suit, and will proceed if it is certified to satisfy four prerequisites: numerosity, commonality, typicality, and adequacy.5 A class-action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
A recent U.S. Supreme Court decision has, however, put a damper on class-action suits by tightening the jurisdictional requirement.6
The case involved Bristol-Myers Squibb, which was sued in California by several hundred individuals from 33 states for injuries from the platelet inhibitor Plavix (clopidogrel). The issue was whether non–California residents could sue in that state for injuries incurred elsewhere.
In a 8-1 decision, the U.S. Supreme Court held that California courts did not have specific jurisdiction to hear the claims of nonresidents without identifying an adequate link between the state and the nonresidents’ claims, as they weren’t prescribed Plavix in the state, didn’t buy or take the drug there, and weren’t injured by the drug there.
Finally, note that, should a doctor fail to warn an injured patient of a known medication risk, the patient may have a claim against the doctor – but usually not against the drug manufacturer. This is termed the “learned-intermediary doctrine.” The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through its sales reps and in its package insert and the Physician’s Desk Reference. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship.
Such lawsuits fall in the common category of medical negligence and lack of informed consent, and are not considered a product liability action.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.
2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.
3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).
4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.
5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.
6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).
QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.
Which of the following statements is incorrect?
A. These are all examples of product liability.
B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.
C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.
D. It is now harder to include multiple plaintiffs in a class-action lawsuit.
E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.
ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.1 DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.
The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”2 Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.
At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.
Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.
The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.
Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.
In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.3 He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.
The California Supreme Court went beyond the law of contracts and negligence by introducing the notion of strict liability, which centers on whether a product is defective and unreasonably dangerous. It holds that a professional supplier who sells a product that is both defective and unreasonably dangerous is strictly liable to foreseeable plaintiffs.
“Defective” is usually defined as product quality that is less than what a reasonable consumer expects. It can be a design, manufacturing, or marketing defect, the latter instance typically showing up as a failure to warn. “Unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Product liability lawsuits commonly involve pharmaceutical products and medical devices. Recent examples are suits against Pfizer over Lipitor’s alleged role as a cause of diabetes and against Johnson & Johnson over its talcum products purportedly causing ovarian cancer.4
When the same product injures multiple plaintiffs, they may band together to file a common legal action against the manufacturer. This is called a class-action suit, and will proceed if it is certified to satisfy four prerequisites: numerosity, commonality, typicality, and adequacy.5 A class-action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
A recent U.S. Supreme Court decision has, however, put a damper on class-action suits by tightening the jurisdictional requirement.6
The case involved Bristol-Myers Squibb, which was sued in California by several hundred individuals from 33 states for injuries from the platelet inhibitor Plavix (clopidogrel). The issue was whether non–California residents could sue in that state for injuries incurred elsewhere.
In a 8-1 decision, the U.S. Supreme Court held that California courts did not have specific jurisdiction to hear the claims of nonresidents without identifying an adequate link between the state and the nonresidents’ claims, as they weren’t prescribed Plavix in the state, didn’t buy or take the drug there, and weren’t injured by the drug there.
Finally, note that, should a doctor fail to warn an injured patient of a known medication risk, the patient may have a claim against the doctor – but usually not against the drug manufacturer. This is termed the “learned-intermediary doctrine.” The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through its sales reps and in its package insert and the Physician’s Desk Reference. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship.
Such lawsuits fall in the common category of medical negligence and lack of informed consent, and are not considered a product liability action.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].
References
1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.
2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.
3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).
4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.
5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.
6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).
Inpatient vs. outpatient addiction treatment: Which is best?
In the course of my general psychiatry practice, there are times when I am unable to manage a patient’s substance abuse issues, and I have referred patients to a higher level of care – often to an intensive outpatient program (IOP) that meets for 3 hours a day, or to an inpatient rehabilitation, usually for 28 days. I’m not always sure who can be managed in which setting, and I usually honor the patient’s wishes. If the patient is motivated, has a support system in place, and is concerned that his job will be in jeopardy if he takes time off work, then I refer to Kolmac Outpatient Recovery Centers, a local outpatient treatment center that gives patients the option of attending in the mornings or evenings and allows most people to continue working. If I think I may have only a single shot at getting a patient engaged in care, and the patient is willing to go to an inpatient setting, I refer to a residential treatment facility. It has occurred to me that this is not a very scientific way of making a treatment decision.
George Kolodner, MD, is the chief clinical officer of Kolmac. He has been a member of the American Society of Addiction Medicine’s (ASAM) treatment criteria committee. When I spoke with Dr. Kolodner, he noted: “Discussions between third-party payers and treatment programs about what is the appropriate level of care for a particular individual have been adversarial. ASAM has spent many years developing the ASAM Criteria, a document that attempts to mediate these disagreements by developing objective criteria for where people ought to be treated. Because it is so comprehensive and the variables are so many, it can be difficult to use. A computerized version, called ‘Continuum,’ has been developed to make the criteria more user-friendly.”
“My 45-year experience,” Dr. Kolodner continued, “is that detoxification and rehabilitation can usually be done successfully on an outpatient basis if an appropriate facility is available and the patient has both a supportive living environment and can get to the treatment. Hospitalization and residential rehabilitation is an essential level of care when those conditions do not exist or when outpatient treatment proves to be insufficient.”
One problem with comparing the success of IOPs to inpatient programs is that these settings differ widely in which services they offer to patients.
“There’s no standardization,” Dr. Kolodner said. “The services may be watered down, they may not have a medical staff or a psychiatrist, and people get sucked into inappropriate treatments. When it comes to both IOPs and inpatient facilities, there is no uniformity, and right now it’s caveat emptor.”
Marc Fishman, MD, is medical director of Maryland Treatment Centers/Mountain Manor Treatment Center, a coeditor of the ASAM Criteria, and, with Dr. Kolodner, a member of ASAM’s treatment criteria committee. He, too, talked about the absence of standardization across treatment settings.
“Bed-based and non–bed-based care exist in many flavors and subflavors. You have to remember,” Dr. Fishman said, “this is a marathon, not a sprint, and one of the most important goals of bed-based care is that it serves as a stepping stone for outpatient treatment.”
Dr. Fishman talked about a list of criteria he uses to decide whether someone can be treated as an outpatient. “First, someone has to be able to access outpatient treatment; it may not be available. Can they get back and forth? How chaotic are their lives? Is there support at home, or is it a toxic environment in which others are using? Are they likely to keep using and drop out? What is the patient’s level of motivation? If a person is very ambivalent, you may need a high-intensity motivational milieu. Are their psychiatric symptoms severe enough to require 24-hour monitoring and supervision? Most detoxification we can do on an outpatient basis, but some complex multisubstance withdrawal may need more monitoring.
“Also, we have an increasing armamentarium of medications to promote abstinence, and sometimes it makes sense to start them in higher-level treatment settings; for example long-acting injectable naltrexone (Vivitrol) needs a 10-day postdetox opioid-free washout before it can be started.”
Dr. Fishman was careful to note that imminent danger is usually not a reason to use an inpatient rehab setting. “When you’re talking about safety issues, then people usually need a hospital. Most rehabs are not equipped to deal with dangerous patients.”
In choosing from the different treatment options, the first question should be to ask which forms of treatment are available with high-quality care. Can the patient access an outpatient center, will he be able to get to treatment, and will he be able to remain sober between visits? Will he be offered a full range of treatment options in that setting? Can substance withdrawal be managed safely? If the patient fails at outpatient care, will he be willing to consider inpatient treatment as a next step? What is the risk associated with relapse in a setting that allows for access to substances between sessions? Is the patient someone who is at high risk for a fatal overdose, or at high risk for endangering others, for example, someone who has been revived from overdoses or has driven while inebriated? Would this patient benefit from more intensive psychotherapeutic care? And the question that always haunts me: If there is a bad outcome, will I regret that I did not recommend more?”
Often, I’m left with the idea that it would be nice if we were all given crystal balls at the end of training. In hindsight, if a patient does well, the treatment that was offered was enough, and perhaps even too much in terms of cost. If a patient does not do well, we may be left to ask if he would have been better off if we had recommended a higher level of care, assuming that care could be financed and accessed, and that the patient complied with the treatment recommendations.
Both experts agree that treatment is often effective, and the news here is good. But treatment only works if a patient actually follows through on it, so the best treatment is often the one the patient is willing to accept.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016).
In the course of my general psychiatry practice, there are times when I am unable to manage a patient’s substance abuse issues, and I have referred patients to a higher level of care – often to an intensive outpatient program (IOP) that meets for 3 hours a day, or to an inpatient rehabilitation, usually for 28 days. I’m not always sure who can be managed in which setting, and I usually honor the patient’s wishes. If the patient is motivated, has a support system in place, and is concerned that his job will be in jeopardy if he takes time off work, then I refer to Kolmac Outpatient Recovery Centers, a local outpatient treatment center that gives patients the option of attending in the mornings or evenings and allows most people to continue working. If I think I may have only a single shot at getting a patient engaged in care, and the patient is willing to go to an inpatient setting, I refer to a residential treatment facility. It has occurred to me that this is not a very scientific way of making a treatment decision.
George Kolodner, MD, is the chief clinical officer of Kolmac. He has been a member of the American Society of Addiction Medicine’s (ASAM) treatment criteria committee. When I spoke with Dr. Kolodner, he noted: “Discussions between third-party payers and treatment programs about what is the appropriate level of care for a particular individual have been adversarial. ASAM has spent many years developing the ASAM Criteria, a document that attempts to mediate these disagreements by developing objective criteria for where people ought to be treated. Because it is so comprehensive and the variables are so many, it can be difficult to use. A computerized version, called ‘Continuum,’ has been developed to make the criteria more user-friendly.”
“My 45-year experience,” Dr. Kolodner continued, “is that detoxification and rehabilitation can usually be done successfully on an outpatient basis if an appropriate facility is available and the patient has both a supportive living environment and can get to the treatment. Hospitalization and residential rehabilitation is an essential level of care when those conditions do not exist or when outpatient treatment proves to be insufficient.”
One problem with comparing the success of IOPs to inpatient programs is that these settings differ widely in which services they offer to patients.
“There’s no standardization,” Dr. Kolodner said. “The services may be watered down, they may not have a medical staff or a psychiatrist, and people get sucked into inappropriate treatments. When it comes to both IOPs and inpatient facilities, there is no uniformity, and right now it’s caveat emptor.”
Marc Fishman, MD, is medical director of Maryland Treatment Centers/Mountain Manor Treatment Center, a coeditor of the ASAM Criteria, and, with Dr. Kolodner, a member of ASAM’s treatment criteria committee. He, too, talked about the absence of standardization across treatment settings.
“Bed-based and non–bed-based care exist in many flavors and subflavors. You have to remember,” Dr. Fishman said, “this is a marathon, not a sprint, and one of the most important goals of bed-based care is that it serves as a stepping stone for outpatient treatment.”
Dr. Fishman talked about a list of criteria he uses to decide whether someone can be treated as an outpatient. “First, someone has to be able to access outpatient treatment; it may not be available. Can they get back and forth? How chaotic are their lives? Is there support at home, or is it a toxic environment in which others are using? Are they likely to keep using and drop out? What is the patient’s level of motivation? If a person is very ambivalent, you may need a high-intensity motivational milieu. Are their psychiatric symptoms severe enough to require 24-hour monitoring and supervision? Most detoxification we can do on an outpatient basis, but some complex multisubstance withdrawal may need more monitoring.
“Also, we have an increasing armamentarium of medications to promote abstinence, and sometimes it makes sense to start them in higher-level treatment settings; for example long-acting injectable naltrexone (Vivitrol) needs a 10-day postdetox opioid-free washout before it can be started.”
Dr. Fishman was careful to note that imminent danger is usually not a reason to use an inpatient rehab setting. “When you’re talking about safety issues, then people usually need a hospital. Most rehabs are not equipped to deal with dangerous patients.”
In choosing from the different treatment options, the first question should be to ask which forms of treatment are available with high-quality care. Can the patient access an outpatient center, will he be able to get to treatment, and will he be able to remain sober between visits? Will he be offered a full range of treatment options in that setting? Can substance withdrawal be managed safely? If the patient fails at outpatient care, will he be willing to consider inpatient treatment as a next step? What is the risk associated with relapse in a setting that allows for access to substances between sessions? Is the patient someone who is at high risk for a fatal overdose, or at high risk for endangering others, for example, someone who has been revived from overdoses or has driven while inebriated? Would this patient benefit from more intensive psychotherapeutic care? And the question that always haunts me: If there is a bad outcome, will I regret that I did not recommend more?”
Often, I’m left with the idea that it would be nice if we were all given crystal balls at the end of training. In hindsight, if a patient does well, the treatment that was offered was enough, and perhaps even too much in terms of cost. If a patient does not do well, we may be left to ask if he would have been better off if we had recommended a higher level of care, assuming that care could be financed and accessed, and that the patient complied with the treatment recommendations.
Both experts agree that treatment is often effective, and the news here is good. But treatment only works if a patient actually follows through on it, so the best treatment is often the one the patient is willing to accept.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016).
In the course of my general psychiatry practice, there are times when I am unable to manage a patient’s substance abuse issues, and I have referred patients to a higher level of care – often to an intensive outpatient program (IOP) that meets for 3 hours a day, or to an inpatient rehabilitation, usually for 28 days. I’m not always sure who can be managed in which setting, and I usually honor the patient’s wishes. If the patient is motivated, has a support system in place, and is concerned that his job will be in jeopardy if he takes time off work, then I refer to Kolmac Outpatient Recovery Centers, a local outpatient treatment center that gives patients the option of attending in the mornings or evenings and allows most people to continue working. If I think I may have only a single shot at getting a patient engaged in care, and the patient is willing to go to an inpatient setting, I refer to a residential treatment facility. It has occurred to me that this is not a very scientific way of making a treatment decision.
George Kolodner, MD, is the chief clinical officer of Kolmac. He has been a member of the American Society of Addiction Medicine’s (ASAM) treatment criteria committee. When I spoke with Dr. Kolodner, he noted: “Discussions between third-party payers and treatment programs about what is the appropriate level of care for a particular individual have been adversarial. ASAM has spent many years developing the ASAM Criteria, a document that attempts to mediate these disagreements by developing objective criteria for where people ought to be treated. Because it is so comprehensive and the variables are so many, it can be difficult to use. A computerized version, called ‘Continuum,’ has been developed to make the criteria more user-friendly.”
“My 45-year experience,” Dr. Kolodner continued, “is that detoxification and rehabilitation can usually be done successfully on an outpatient basis if an appropriate facility is available and the patient has both a supportive living environment and can get to the treatment. Hospitalization and residential rehabilitation is an essential level of care when those conditions do not exist or when outpatient treatment proves to be insufficient.”
One problem with comparing the success of IOPs to inpatient programs is that these settings differ widely in which services they offer to patients.
“There’s no standardization,” Dr. Kolodner said. “The services may be watered down, they may not have a medical staff or a psychiatrist, and people get sucked into inappropriate treatments. When it comes to both IOPs and inpatient facilities, there is no uniformity, and right now it’s caveat emptor.”
Marc Fishman, MD, is medical director of Maryland Treatment Centers/Mountain Manor Treatment Center, a coeditor of the ASAM Criteria, and, with Dr. Kolodner, a member of ASAM’s treatment criteria committee. He, too, talked about the absence of standardization across treatment settings.
“Bed-based and non–bed-based care exist in many flavors and subflavors. You have to remember,” Dr. Fishman said, “this is a marathon, not a sprint, and one of the most important goals of bed-based care is that it serves as a stepping stone for outpatient treatment.”
Dr. Fishman talked about a list of criteria he uses to decide whether someone can be treated as an outpatient. “First, someone has to be able to access outpatient treatment; it may not be available. Can they get back and forth? How chaotic are their lives? Is there support at home, or is it a toxic environment in which others are using? Are they likely to keep using and drop out? What is the patient’s level of motivation? If a person is very ambivalent, you may need a high-intensity motivational milieu. Are their psychiatric symptoms severe enough to require 24-hour monitoring and supervision? Most detoxification we can do on an outpatient basis, but some complex multisubstance withdrawal may need more monitoring.
“Also, we have an increasing armamentarium of medications to promote abstinence, and sometimes it makes sense to start them in higher-level treatment settings; for example long-acting injectable naltrexone (Vivitrol) needs a 10-day postdetox opioid-free washout before it can be started.”
Dr. Fishman was careful to note that imminent danger is usually not a reason to use an inpatient rehab setting. “When you’re talking about safety issues, then people usually need a hospital. Most rehabs are not equipped to deal with dangerous patients.”
In choosing from the different treatment options, the first question should be to ask which forms of treatment are available with high-quality care. Can the patient access an outpatient center, will he be able to get to treatment, and will he be able to remain sober between visits? Will he be offered a full range of treatment options in that setting? Can substance withdrawal be managed safely? If the patient fails at outpatient care, will he be willing to consider inpatient treatment as a next step? What is the risk associated with relapse in a setting that allows for access to substances between sessions? Is the patient someone who is at high risk for a fatal overdose, or at high risk for endangering others, for example, someone who has been revived from overdoses or has driven while inebriated? Would this patient benefit from more intensive psychotherapeutic care? And the question that always haunts me: If there is a bad outcome, will I regret that I did not recommend more?”
Often, I’m left with the idea that it would be nice if we were all given crystal balls at the end of training. In hindsight, if a patient does well, the treatment that was offered was enough, and perhaps even too much in terms of cost. If a patient does not do well, we may be left to ask if he would have been better off if we had recommended a higher level of care, assuming that care could be financed and accessed, and that the patient complied with the treatment recommendations.
Both experts agree that treatment is often effective, and the news here is good. But treatment only works if a patient actually follows through on it, so the best treatment is often the one the patient is willing to accept.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016).
Slowing down
This past Labor Day weekend, I did something radical. I slowed down. Way down. My wife slowed down with me, which helped. We spent the weekend close to home walking, talking, reading, contemplating, planning, assessing, doing puzzles and crosswords, and imbibing a craft beer or two, slowly, of course. Why? Because of Adam Grant, PhD, the organizational psychologist at the University of Pennsylvania’s Wharton School of Business, Philadelphia. I had recently reread his 2016 book I’m a big fan; he’s one of those professors who makes you fervently wish you were a student again, someone who will provoke you and challenge your way of thinking.
Dr. Grant’s basic premise, which he has proved through research, is that procrastination boosts productivity. Here’s how: Let’s say you’re facing a challenge or difficult task. He says to start working on it immediately, then take some time away for reflection. This “quick to start and slow to finish” method allows your brain to continually percolate on the problem. An incomplete task stays partially active in your brain. When you come back to it you often see it with fresh eyes. You will experience your highest productivity when you are toggling between these two modes.
This makes sense, and Dr. Grant cites numerous examples from Leonardo da Vinci to the founders of Warby-Parker, as examples of success. But how can it benefit physicians? Many of us are “precrastinators,” people who tend to complete or at least begin tasks as soon as possible, even when it’s unnecessary or not urgent. Unlike some jobs in which it’s easier to take a break from a project and return to it with more creative solutions, we often are racing against a clock to see more patients, read more slides, answer more emails, and make more phone calls. We are perpetually frenetic, which is not conducive to original thinking.
If this sounds like you, then you are likely to benefit from deliberate procrastination. Here are a few ways to slow down:
- Put it on your calendar. Yes, I see the irony, but it works. Start by scheduling one hour a week where you are to accomplish nothing. You can fill this time with whatever your mind wants to do at that moment.
- When faced with a diagnostic dilemma or treatment failure, resist the urge to solve that problem in that moment. Save that note for later, tell the patient you will call him back or bring him back for a visit later. Even if you’re not actively working on it, it will incubate somewhere in your brain, allowing more divergent thought processes to take over. It’s a little like trying to solve a crossword that seems impossible in the moment and then answers suddenly appear without effort.
- Take up a hobby: Play the guitar, learn to make pasta, climb a big rock. When you are fully engaged in such pursuits it requires complete mental focus. When you revisit the difficult problem you’re working on, you will likely see it from different perspectives.
- Meditate: Meditation requires our brains and bodies to slow down. It can help reduce self-doubt and criticism which stifle problem solving.
- Watch Slow TV. Slow TV is a Scandinavian phenomenon where you sit and watch meditative video such as a 7-hour train cam from Bergen, Norway, to Oslo. There’s no dialogue, no plot, no commercials. It’s just 7 hours of track and train and is weirdly comforting.
If you want to learn more, then when you get a chance, Google “slow living” and explore. Of course, some of you precrastinators probably have already started before finishing this column.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
This past Labor Day weekend, I did something radical. I slowed down. Way down. My wife slowed down with me, which helped. We spent the weekend close to home walking, talking, reading, contemplating, planning, assessing, doing puzzles and crosswords, and imbibing a craft beer or two, slowly, of course. Why? Because of Adam Grant, PhD, the organizational psychologist at the University of Pennsylvania’s Wharton School of Business, Philadelphia. I had recently reread his 2016 book I’m a big fan; he’s one of those professors who makes you fervently wish you were a student again, someone who will provoke you and challenge your way of thinking.
Dr. Grant’s basic premise, which he has proved through research, is that procrastination boosts productivity. Here’s how: Let’s say you’re facing a challenge or difficult task. He says to start working on it immediately, then take some time away for reflection. This “quick to start and slow to finish” method allows your brain to continually percolate on the problem. An incomplete task stays partially active in your brain. When you come back to it you often see it with fresh eyes. You will experience your highest productivity when you are toggling between these two modes.
This makes sense, and Dr. Grant cites numerous examples from Leonardo da Vinci to the founders of Warby-Parker, as examples of success. But how can it benefit physicians? Many of us are “precrastinators,” people who tend to complete or at least begin tasks as soon as possible, even when it’s unnecessary or not urgent. Unlike some jobs in which it’s easier to take a break from a project and return to it with more creative solutions, we often are racing against a clock to see more patients, read more slides, answer more emails, and make more phone calls. We are perpetually frenetic, which is not conducive to original thinking.
If this sounds like you, then you are likely to benefit from deliberate procrastination. Here are a few ways to slow down:
- Put it on your calendar. Yes, I see the irony, but it works. Start by scheduling one hour a week where you are to accomplish nothing. You can fill this time with whatever your mind wants to do at that moment.
- When faced with a diagnostic dilemma or treatment failure, resist the urge to solve that problem in that moment. Save that note for later, tell the patient you will call him back or bring him back for a visit later. Even if you’re not actively working on it, it will incubate somewhere in your brain, allowing more divergent thought processes to take over. It’s a little like trying to solve a crossword that seems impossible in the moment and then answers suddenly appear without effort.
- Take up a hobby: Play the guitar, learn to make pasta, climb a big rock. When you are fully engaged in such pursuits it requires complete mental focus. When you revisit the difficult problem you’re working on, you will likely see it from different perspectives.
- Meditate: Meditation requires our brains and bodies to slow down. It can help reduce self-doubt and criticism which stifle problem solving.
- Watch Slow TV. Slow TV is a Scandinavian phenomenon where you sit and watch meditative video such as a 7-hour train cam from Bergen, Norway, to Oslo. There’s no dialogue, no plot, no commercials. It’s just 7 hours of track and train and is weirdly comforting.
If you want to learn more, then when you get a chance, Google “slow living” and explore. Of course, some of you precrastinators probably have already started before finishing this column.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
This past Labor Day weekend, I did something radical. I slowed down. Way down. My wife slowed down with me, which helped. We spent the weekend close to home walking, talking, reading, contemplating, planning, assessing, doing puzzles and crosswords, and imbibing a craft beer or two, slowly, of course. Why? Because of Adam Grant, PhD, the organizational psychologist at the University of Pennsylvania’s Wharton School of Business, Philadelphia. I had recently reread his 2016 book I’m a big fan; he’s one of those professors who makes you fervently wish you were a student again, someone who will provoke you and challenge your way of thinking.
Dr. Grant’s basic premise, which he has proved through research, is that procrastination boosts productivity. Here’s how: Let’s say you’re facing a challenge or difficult task. He says to start working on it immediately, then take some time away for reflection. This “quick to start and slow to finish” method allows your brain to continually percolate on the problem. An incomplete task stays partially active in your brain. When you come back to it you often see it with fresh eyes. You will experience your highest productivity when you are toggling between these two modes.
This makes sense, and Dr. Grant cites numerous examples from Leonardo da Vinci to the founders of Warby-Parker, as examples of success. But how can it benefit physicians? Many of us are “precrastinators,” people who tend to complete or at least begin tasks as soon as possible, even when it’s unnecessary or not urgent. Unlike some jobs in which it’s easier to take a break from a project and return to it with more creative solutions, we often are racing against a clock to see more patients, read more slides, answer more emails, and make more phone calls. We are perpetually frenetic, which is not conducive to original thinking.
If this sounds like you, then you are likely to benefit from deliberate procrastination. Here are a few ways to slow down:
- Put it on your calendar. Yes, I see the irony, but it works. Start by scheduling one hour a week where you are to accomplish nothing. You can fill this time with whatever your mind wants to do at that moment.
- When faced with a diagnostic dilemma or treatment failure, resist the urge to solve that problem in that moment. Save that note for later, tell the patient you will call him back or bring him back for a visit later. Even if you’re not actively working on it, it will incubate somewhere in your brain, allowing more divergent thought processes to take over. It’s a little like trying to solve a crossword that seems impossible in the moment and then answers suddenly appear without effort.
- Take up a hobby: Play the guitar, learn to make pasta, climb a big rock. When you are fully engaged in such pursuits it requires complete mental focus. When you revisit the difficult problem you’re working on, you will likely see it from different perspectives.
- Meditate: Meditation requires our brains and bodies to slow down. It can help reduce self-doubt and criticism which stifle problem solving.
- Watch Slow TV. Slow TV is a Scandinavian phenomenon where you sit and watch meditative video such as a 7-hour train cam from Bergen, Norway, to Oslo. There’s no dialogue, no plot, no commercials. It’s just 7 hours of track and train and is weirdly comforting.
If you want to learn more, then when you get a chance, Google “slow living” and explore. Of course, some of you precrastinators probably have already started before finishing this column.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
Spurring innovation in digital health
Owing to digital advances, we’re experiencing a reimagination of health care delivery. Consumers are now empowered to take more control of their own health information to make better informed decisions about their medical care and healthy living. These advances enable better health outcomes for patients.
This opportunity is supported by a new technological paradigm of digital health tools, like apps, that enable consumers to have more active engagement and access to real-time information about their health and activities. These tools allow consumers and providers to supersede the traditional, physical constraints of health care delivery and make the most of the opportunities offered by mobile technology.
With these advances has come a new swath of companies that are investing in these new opportunities. These firms may be new to health care products and may not be accustomed to navigating the regulatory landscape that has traditionally surrounded these areas. A great example is the announcement of two mobile medical apps designed by Apple to work on the Apple Watch. One app creates an electrocardiogram, similar to traditional electrocardiograms, to detect the presence of atrial fibrillation and regular heart rhythm, while the other app analyzes pulse rate data to identify irregular heart rhythms suggestive of atrial fibrillation and notify the user. The FDA [Food and Drug Administration] worked closely with the company as they developed and tested these software products, which may help millions of users identify health concerns more quickly. Health care products on ubiquitous devices, like smartwatches, may help users seek treatment earlier and will truly empower them with more information about their health.
In the last few years, the FDA has been taking steps to encourage more development and greater innovation in the digital health space. With the launch of our Digital Health Innovation Action Plan last summer, we committed to implementing policies, adding expertise, and exploring a software precertification pilot program to bring clarity and efficiency to how we regulate digital health products.
This commitment is not only reflected in actions like approving or clearing new apps and launching our Digital Health Innovation Action Plan but also in what we hope to do in the future. That’s why in the FDA’s Fiscal Year 2019 Budget, we proposed to create a Center of Excellence for Digital Health that would advance modernizing our regulatory approach to help this industry grow and reach its full potential, while protecting patients.
Dr. Gottlieb is commissioner of the FDA and Dr. Shuren in director of the FDA Center for Devices and Radiological Health. Their comments are excerpted from an FDA statement released Sept. 12, 2018.
Owing to digital advances, we’re experiencing a reimagination of health care delivery. Consumers are now empowered to take more control of their own health information to make better informed decisions about their medical care and healthy living. These advances enable better health outcomes for patients.
This opportunity is supported by a new technological paradigm of digital health tools, like apps, that enable consumers to have more active engagement and access to real-time information about their health and activities. These tools allow consumers and providers to supersede the traditional, physical constraints of health care delivery and make the most of the opportunities offered by mobile technology.
With these advances has come a new swath of companies that are investing in these new opportunities. These firms may be new to health care products and may not be accustomed to navigating the regulatory landscape that has traditionally surrounded these areas. A great example is the announcement of two mobile medical apps designed by Apple to work on the Apple Watch. One app creates an electrocardiogram, similar to traditional electrocardiograms, to detect the presence of atrial fibrillation and regular heart rhythm, while the other app analyzes pulse rate data to identify irregular heart rhythms suggestive of atrial fibrillation and notify the user. The FDA [Food and Drug Administration] worked closely with the company as they developed and tested these software products, which may help millions of users identify health concerns more quickly. Health care products on ubiquitous devices, like smartwatches, may help users seek treatment earlier and will truly empower them with more information about their health.
In the last few years, the FDA has been taking steps to encourage more development and greater innovation in the digital health space. With the launch of our Digital Health Innovation Action Plan last summer, we committed to implementing policies, adding expertise, and exploring a software precertification pilot program to bring clarity and efficiency to how we regulate digital health products.
This commitment is not only reflected in actions like approving or clearing new apps and launching our Digital Health Innovation Action Plan but also in what we hope to do in the future. That’s why in the FDA’s Fiscal Year 2019 Budget, we proposed to create a Center of Excellence for Digital Health that would advance modernizing our regulatory approach to help this industry grow and reach its full potential, while protecting patients.
Dr. Gottlieb is commissioner of the FDA and Dr. Shuren in director of the FDA Center for Devices and Radiological Health. Their comments are excerpted from an FDA statement released Sept. 12, 2018.
Owing to digital advances, we’re experiencing a reimagination of health care delivery. Consumers are now empowered to take more control of their own health information to make better informed decisions about their medical care and healthy living. These advances enable better health outcomes for patients.
This opportunity is supported by a new technological paradigm of digital health tools, like apps, that enable consumers to have more active engagement and access to real-time information about their health and activities. These tools allow consumers and providers to supersede the traditional, physical constraints of health care delivery and make the most of the opportunities offered by mobile technology.
With these advances has come a new swath of companies that are investing in these new opportunities. These firms may be new to health care products and may not be accustomed to navigating the regulatory landscape that has traditionally surrounded these areas. A great example is the announcement of two mobile medical apps designed by Apple to work on the Apple Watch. One app creates an electrocardiogram, similar to traditional electrocardiograms, to detect the presence of atrial fibrillation and regular heart rhythm, while the other app analyzes pulse rate data to identify irregular heart rhythms suggestive of atrial fibrillation and notify the user. The FDA [Food and Drug Administration] worked closely with the company as they developed and tested these software products, which may help millions of users identify health concerns more quickly. Health care products on ubiquitous devices, like smartwatches, may help users seek treatment earlier and will truly empower them with more information about their health.
In the last few years, the FDA has been taking steps to encourage more development and greater innovation in the digital health space. With the launch of our Digital Health Innovation Action Plan last summer, we committed to implementing policies, adding expertise, and exploring a software precertification pilot program to bring clarity and efficiency to how we regulate digital health products.
This commitment is not only reflected in actions like approving or clearing new apps and launching our Digital Health Innovation Action Plan but also in what we hope to do in the future. That’s why in the FDA’s Fiscal Year 2019 Budget, we proposed to create a Center of Excellence for Digital Health that would advance modernizing our regulatory approach to help this industry grow and reach its full potential, while protecting patients.
Dr. Gottlieb is commissioner of the FDA and Dr. Shuren in director of the FDA Center for Devices and Radiological Health. Their comments are excerpted from an FDA statement released Sept. 12, 2018.