Current Psychiatry

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...

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...

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...

Henry A. Nasrallah, MD
Editor-in-Chief

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

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. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
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

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 malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
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, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

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. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
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

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 malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
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, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

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. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
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

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 malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
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.

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

During my residency training, I was trained in the standard “reactive” psychiatric consultation model. In this system, I would see consults placed by the primary team after they identified a behavioral issue in a patient. As a trainee, I experienced frequent frustrations working in this model: Consults that are discharge-dependent (“Can you see the patient before he is discharged this morning?”), consults for acute behavioral dysregulation (“The patient is near the elevator, can you come see him ASAP?”), or consults for consequences of poor management of alcohol/benzodiazepine withdrawal (“The patient is confused and trying to leave”).

As a fellow in consultation-liaison (C-L) psychiatry, I was introduced to the “proactive” consultation model, which avoids some of these issues. In this article, which is intended for residents who have not been exposed to this new approach, I explain how the proactive model changes our experience as C-L clinicians.

The Behavioral Intervention Team

At Yale New Haven Hospital, the Behavioral Intervention Team (BIT) is a proactive, multidisciplinary psychiatric consultation service that serves the internal medicine units at the hospital. The team consists of nurse practitioners, nurse liaison specialists, social workers, and psychiatrists. The team identifies and removes behavioral barriers in the care of hospitalized mentally ill patients.

The BIT collaborates closely with the medical team through formal and informal consultation; co-management of behavioral issues; education of medical, nursing, and social work staff; and direct care of complex patients with behavioral disorders. The BIT assists the medical team with transitions to appropriate outpatient and inpatient psychiatric care. The team also manages the relationship with the insurer when a patient requires a stay in a psychiatric unit.

This model has a critical financial benefit in reducing the length of stay, but it also has many other benefits. It focuses on early recognition and treatment, and helps mitigate the effects of mental or substance use disorders on patients’ recovery. BIT members educate their peers regarding management of a multitude of behavioral issues. This fosters extensive informal collaboration (“curbside consultation”), which helps patients who did not receive a formal consult. The model distributes work more rationally among different professional specialists. It yields a relationship with medical teams that is not only more effective, but also more enjoyable. In the BIT model, psychiatrists pick the cases where they feel they can have the most impact, and avoid the cases they feel they cannot have any.^1-3

CASE A better approach to alcohol withdrawal

Mr. X, age 56, has a history of alcohol use disorder, hypertension, and coronary artery disease. He’s had multiple past admissions for complicated alcohol withdrawal. He is transferred from a local community hospital, where he had presented with chest pain. His last drink was 2 days prior to admission, and his blood alcohol level is <10 mg/dL.

During Mr. X’s previous hospitalizations, psychiatric consults were performed in the standard reactive model. The primary team initially prescribed an ineffective dosage of benzodiazepines for his alcohol withdrawal. This escalated his withdrawal into delirium tremens, after which psychiatry was involved. Due to this early ineffective management, the patient had a prolonged medical ICU stay and overall stay, experienced increased medical complications, and required increased staff resources because he was extremely agitated.

Continued to: During this hospitalization...

During this hospitalization, Mr. X arrives with similar medical complaints. The nurse practitioner on the BIT service, who screened all admissions each day, examines the prior notes (she finds the team sign-outs to be particularly useful). She suggests a psychiatric consult on Day 1 of the admission, which the primary medical team orders. The BIT nurse practitioner gives apt recommendations of evidence-based management, including a benzodiazepine taper, high-dose thiamine, and psychopharmacologic approaches to severe agitation. The nurse liaison specialist on the service makes behavioral plans for managing agitation, which she communicates to the nurses caring for Mr. X.

Because his withdrawal is managed more promptly, Mr. X’s length of stay is shorter and he does not experience any medical complications. The BIT social worker helps find appropriate aftercare options, including residential treatment and Alcoholics Anonymous meetings, to which the patient agrees.

Participating in this case was highly educational for me as a trainee. This case is but one example among many where proactive consultation provided prompt care, lowered the rate of complications, reduced length of stay, and resulted in greater provider satisfaction. The Table⁴ contrasts the proactive and reactive consultation models. The following 5 factors are critical in the proactive consultation model^4,5:

1. Standardized and reliable procedure screening of all admissions, involving a mental health professional, through record review and staff contact. This screening should identify patients with issues who will benefit specifically from in-hospital services, rather than just patients with any psychiatric issue. An electronic medical record is essential to efficient screening, team communication, and progress monitoring. Truly integrated consultation would be impossible with a paper chart.

Research has shown the effectiveness of proactive, embedded, multidisciplinary approaches.^1-3,5 It was a gratifying experience to work in this model. I worked intimately with medical clinicians, and shared the burden of responsibilities leading to optimal patient outcomes. The proactive consultation model truly re-emphasizes the “liaison” component of C-L psychiatry, as it was originally envisioned.

Computational psychiatry is an emerging field in which artificial intelligence and machine learning are used to find hidden patterns in big data to better understand, predict, and treat mental illness. The field uses various mathematical models to predict the dependent variable y based on the independent variable x. One application of analytics in medicine was the Framingham Heart Study, which used multivariate logistic regression to predict heart disease.¹

Analytics could be used to predict the number of bad outcomes associated with different psychiatric medications over time. To demonstrate this, I examined a select data set of 8 psychiatric medications (aripiprazole, ziprasidone, risperidone, olanzapine, sertraline, trazodone, amitriptyline, and lithium) accounting for 59,827 bad outcomes during a 15-year period as reported by U.S. poison control centers,² and plotted these on the y-axis.

When considering the independent variable to use as a predictor for bad outcomes, I used a composite index derived with the relative lethality (RL) equation, f(x) = 310x /LD50, where x is the daily dose of a medication prescribed for 30 days, and LD50 is the rat oral lethal dose 50.³ I plotted the RL of the 8 medications on the x-axis. Then I attempted to find a mathematical function that would best fit the x and y intersection points (Figure 1). I used the Excel data analysis pack to run a logarithmic regression model (Figure 2).

The model predicts that medications with a lower RL will have fewer serious outcomes, including mortality. The coefficient of determination r² = 0.968, which indicates that 97% of the variation in serious outcomes is attributed to variation in RL, and 3% may be due to other factors, such as the poor quality of U.S. poison control data. This is a very significant correlation, and the causality is self-evident.

Continued to: The distribution of bad outcomes in the model was...

The distribution of bad outcomes in the model was: 1,446 for aripiprazole (RL = 9.76%), 2,387 for ziprasidone (RL = 24.80%), 5,352 for risperidone (RL = 32.63%), 5,798 for olanzapine (RL = 35.03%), 6,120 for sertraline (RL = 46.72%), 10,343 for trazodone (RL = 269.57%), 13,345 for amitriptyline (RL = 387.50%), and 15,036 for lithium (RL = 1,062.86%). The regression equation is: serious outcomes = –5,677.7 + 3,015.7 × ln (RL).

Some doctors may argue that such a data set is too small to make a meaningful model. However, the number of possible ways of ranking the drugs by bad outcomes is 8! = 40,320, so the probability of guessing the right sequence is P = .000024801. To appreciate how small this probability is, imagine trying to find a person of interest in half a football stadium on Superbowl Sunday.

The RL composite index correctly predicted the ranking order of serious outcomes for the 8 medications and may be useful for finding such outcomes in any drug class. For example, with angiotensin-converting enzyme inhibitors (n = 11) the number of possible combinations is 11! = 39,916,800. The probability of guessing the right sequence is like finding a person of interest in Poland. The model predicts the following decreasing sequence: 1) captopril, 2) fosinopril, 3) quinapril, 4) benazepril, 5) enalapril, 6) lisinopril, 7) moexipril, 8) perindopril, 9) cilazapril, 10) ramipril, 11) trandolapril. The predicted number of bad outcomes is highest for captopril, and lowest for trandolapril. The usefulness of the machine learning algorithm becomes immediately apparent.

Data can inform prescribing

Analytics can expose a critical flaw in the academic psychiatry paradigm for prescribing medications. For example, some doctors may regard lithium as the “gold standard” for treating certain mood disorders, but there is evidence that olanzapine is “significantly more effective than lithium in preventing recurrence of manic and mixed episodes.”⁴ Olanzapine is also 30 times safer than lithium based on its RL index, and had 9,238 fewer bad outcomes based on the 15-year data from U.S. poison control centers.² A patient who intends to attempt suicide would easily be able to find the lethal dose of lithium from a “suicide” web site, and would quickly be able to figure out that the monthly amount of lithium his or her psychiatrist prescribed, would exceed the lethal dose.

When academia and reality collide, the use of analytics will have the final word by preventing suicide in the short term and reducing the number of bad outcomes in the long term. The irony of data science is that mathematical models can find optimal solutions to complex problems in a fraction of a second, but it may take years for a paradigm shift.

Computational psychiatry is an emerging field in which artificial intelligence and machine learning are used to find hidden patterns in big data to better understand, predict, and treat mental illness. The field uses various mathematical models to predict the dependent variable y based on the independent variable x. One application of analytics in medicine was the Framingham Heart Study, which used multivariate logistic regression to predict heart disease.¹

Analytics could be used to predict the number of bad outcomes associated with different psychiatric medications over time. To demonstrate this, I examined a select data set of 8 psychiatric medications (aripiprazole, ziprasidone, risperidone, olanzapine, sertraline, trazodone, amitriptyline, and lithium) accounting for 59,827 bad outcomes during a 15-year period as reported by U.S. poison control centers,² and plotted these on the y-axis.

When considering the independent variable to use as a predictor for bad outcomes, I used a composite index derived with the relative lethality (RL) equation, f(x) = 310x /LD50, where x is the daily dose of a medication prescribed for 30 days, and LD50 is the rat oral lethal dose 50.³ I plotted the RL of the 8 medications on the x-axis. Then I attempted to find a mathematical function that would best fit the x and y intersection points (Figure 1). I used the Excel data analysis pack to run a logarithmic regression model (Figure 2).

The model predicts that medications with a lower RL will have fewer serious outcomes, including mortality. The coefficient of determination r² = 0.968, which indicates that 97% of the variation in serious outcomes is attributed to variation in RL, and 3% may be due to other factors, such as the poor quality of U.S. poison control data. This is a very significant correlation, and the causality is self-evident.

Continued to: The distribution of bad outcomes in the model was...

The distribution of bad outcomes in the model was: 1,446 for aripiprazole (RL = 9.76%), 2,387 for ziprasidone (RL = 24.80%), 5,352 for risperidone (RL = 32.63%), 5,798 for olanzapine (RL = 35.03%), 6,120 for sertraline (RL = 46.72%), 10,343 for trazodone (RL = 269.57%), 13,345 for amitriptyline (RL = 387.50%), and 15,036 for lithium (RL = 1,062.86%). The regression equation is: serious outcomes = –5,677.7 + 3,015.7 × ln (RL).

Some doctors may argue that such a data set is too small to make a meaningful model. However, the number of possible ways of ranking the drugs by bad outcomes is 8! = 40,320, so the probability of guessing the right sequence is P = .000024801. To appreciate how small this probability is, imagine trying to find a person of interest in half a football stadium on Superbowl Sunday.

The RL composite index correctly predicted the ranking order of serious outcomes for the 8 medications and may be useful for finding such outcomes in any drug class. For example, with angiotensin-converting enzyme inhibitors (n = 11) the number of possible combinations is 11! = 39,916,800. The probability of guessing the right sequence is like finding a person of interest in Poland. The model predicts the following decreasing sequence: 1) captopril, 2) fosinopril, 3) quinapril, 4) benazepril, 5) enalapril, 6) lisinopril, 7) moexipril, 8) perindopril, 9) cilazapril, 10) ramipril, 11) trandolapril. The predicted number of bad outcomes is highest for captopril, and lowest for trandolapril. The usefulness of the machine learning algorithm becomes immediately apparent.

Data can inform prescribing

Analytics can expose a critical flaw in the academic psychiatry paradigm for prescribing medications. For example, some doctors may regard lithium as the “gold standard” for treating certain mood disorders, but there is evidence that olanzapine is “significantly more effective than lithium in preventing recurrence of manic and mixed episodes.”⁴ Olanzapine is also 30 times safer than lithium based on its RL index, and had 9,238 fewer bad outcomes based on the 15-year data from U.S. poison control centers.² A patient who intends to attempt suicide would easily be able to find the lethal dose of lithium from a “suicide” web site, and would quickly be able to figure out that the monthly amount of lithium his or her psychiatrist prescribed, would exceed the lethal dose.

When academia and reality collide, the use of analytics will have the final word by preventing suicide in the short term and reducing the number of bad outcomes in the long term. The irony of data science is that mathematical models can find optimal solutions to complex problems in a fraction of a second, but it may take years for a paradigm shift.

Computational psychiatry is an emerging field in which artificial intelligence and machine learning are used to find hidden patterns in big data to better understand, predict, and treat mental illness. The field uses various mathematical models to predict the dependent variable y based on the independent variable x. One application of analytics in medicine was the Framingham Heart Study, which used multivariate logistic regression to predict heart disease.¹

Analytics could be used to predict the number of bad outcomes associated with different psychiatric medications over time. To demonstrate this, I examined a select data set of 8 psychiatric medications (aripiprazole, ziprasidone, risperidone, olanzapine, sertraline, trazodone, amitriptyline, and lithium) accounting for 59,827 bad outcomes during a 15-year period as reported by U.S. poison control centers,² and plotted these on the y-axis.

When considering the independent variable to use as a predictor for bad outcomes, I used a composite index derived with the relative lethality (RL) equation, f(x) = 310x /LD50, where x is the daily dose of a medication prescribed for 30 days, and LD50 is the rat oral lethal dose 50.³ I plotted the RL of the 8 medications on the x-axis. Then I attempted to find a mathematical function that would best fit the x and y intersection points (Figure 1). I used the Excel data analysis pack to run a logarithmic regression model (Figure 2).

The model predicts that medications with a lower RL will have fewer serious outcomes, including mortality. The coefficient of determination r² = 0.968, which indicates that 97% of the variation in serious outcomes is attributed to variation in RL, and 3% may be due to other factors, such as the poor quality of U.S. poison control data. This is a very significant correlation, and the causality is self-evident.

Continued to: The distribution of bad outcomes in the model was...

The distribution of bad outcomes in the model was: 1,446 for aripiprazole (RL = 9.76%), 2,387 for ziprasidone (RL = 24.80%), 5,352 for risperidone (RL = 32.63%), 5,798 for olanzapine (RL = 35.03%), 6,120 for sertraline (RL = 46.72%), 10,343 for trazodone (RL = 269.57%), 13,345 for amitriptyline (RL = 387.50%), and 15,036 for lithium (RL = 1,062.86%). The regression equation is: serious outcomes = –5,677.7 + 3,015.7 × ln (RL).

Some doctors may argue that such a data set is too small to make a meaningful model. However, the number of possible ways of ranking the drugs by bad outcomes is 8! = 40,320, so the probability of guessing the right sequence is P = .000024801. To appreciate how small this probability is, imagine trying to find a person of interest in half a football stadium on Superbowl Sunday.

The RL composite index correctly predicted the ranking order of serious outcomes for the 8 medications and may be useful for finding such outcomes in any drug class. For example, with angiotensin-converting enzyme inhibitors (n = 11) the number of possible combinations is 11! = 39,916,800. The probability of guessing the right sequence is like finding a person of interest in Poland. The model predicts the following decreasing sequence: 1) captopril, 2) fosinopril, 3) quinapril, 4) benazepril, 5) enalapril, 6) lisinopril, 7) moexipril, 8) perindopril, 9) cilazapril, 10) ramipril, 11) trandolapril. The predicted number of bad outcomes is highest for captopril, and lowest for trandolapril. The usefulness of the machine learning algorithm becomes immediately apparent.

Data can inform prescribing

Analytics can expose a critical flaw in the academic psychiatry paradigm for prescribing medications. For example, some doctors may regard lithium as the “gold standard” for treating certain mood disorders, but there is evidence that olanzapine is “significantly more effective than lithium in preventing recurrence of manic and mixed episodes.”⁴ Olanzapine is also 30 times safer than lithium based on its RL index, and had 9,238 fewer bad outcomes based on the 15-year data from U.S. poison control centers.² A patient who intends to attempt suicide would easily be able to find the lethal dose of lithium from a “suicide” web site, and would quickly be able to figure out that the monthly amount of lithium his or her psychiatrist prescribed, would exceed the lethal dose.

When academia and reality collide, the use of analytics will have the final word by preventing suicide in the short term and reducing the number of bad outcomes in the long term. The irony of data science is that mathematical models can find optimal solutions to complex problems in a fraction of a second, but it may take years for a paradigm shift.

Mr. M, age 55, presents to his primary care physician (PCP) with hematochezia. Mr. M states that for the past week, he has noticed blood upon wiping after a bowel movement and is worried that he might have cancer.

Mr. M has a 10-year history of opioid use disorder as diagnosed by his psychiatrist. He is presently maintained on long-acting injectable naltrexone, 380 mg IM every 4 weeks, and has not used opioids for the past 1.5 years. Mr. M is also taking simvastatin, 40 mg, for dyslipidemia, lisinopril, 5 mg, for hypertension, and cetirizine, 5 mg as needed, for seasonal allergies.

A standard workup including a physical examination and laboratory tests are performed. Mr. M’s PCP would like for him to undergo a colonoscopy to investigate the etiology of the bleeding. In consultation with both the PCP and psychiatrist, the gastroenterologist determines that the colonoscopy can be performed within 48 hours with no changes to Mr. M’s medication regimen. The gastroenterologist utilizes a nonopioid, ketorolac, 30 mg IV, for pain management during the procedure. Diverticula were identified in the lower gastrointestinal tract and are treated endoscopically. Mr. M is successfully withdrawn from sedation with no adverse events or pain and continues to be in opioid remission.

Naltrexone competitively antagonizes opioid receptors with the highest affinity for the µ-opioid receptor. It is approved for treatment of alcohol and opioid dependence following opioid detoxification.¹ Its competitive inhibition at the µ-opioid receptor results in the inhibition of exogenous opioid effects. The medication is available as an orally administered tablet as well as a long-acting injection administered intramuscularly (Table 1¹). The long-acting injection can be useful in patients who have difficulty with adherence, because good adherence to naltrexone is required to maximize efficacy.

Due to its ability to block opioid analgesic effects, naltrexone presents a unique challenge for patients taking it who need to undergo procedures that require pain control. Pharmacologic regimens used during procedures often contain a sedative agent, such as propofol, and an opioid for analgesia. Alternative strategies are needed for patients taking naltrexone who require an opioid analgesic agent for procedures such as colonoscopies.

One strategy could be to withhold naltrexone before the procedure to ensure that the medication will not compete with the opioid agent to relieve pain. This strategy depends on the urgency of the procedure, the formulation of naltrexone being used, and patient-specific factors that may increase the risk for adverse events. For a non-urgent, elective procedure, it may be acceptable to hold oral naltrexone approximately 72 hours before the procedure. However, this is likely not a favorable approach for patients who may be at high risk for relapse or for patients who are receiving the long-acting formulation. Additionally, the use of an opioid agent intra- or post-operatively for pain may increase the risk of relapse. The use of opioids for such procedures may also be more difficult in a patient with a history of opioid abuse or dependence because he or she may have developed tolerance to opioids. Conversely, if a patient has been treated with naltrexone for an extended period, a lack of tolerance may increase the risk of respiratory depression with opioid administration due to upregulation of the opioid receptor.²

Continue to: Nonopioid analgesic agents

For a patient receiving naltrexone who needs to undergo a procedure, a multi­disciplinary consultation between the patient’s psychiatrist and other clinicians is key for providing a regimen that is safe and effective. A nonopioid analgesic agent may be considered to avoid the problematic interactions possible in these patients (Table 2^3-5). Nonopioid regimens can be utilized alone or in combination, and may include the following^3-5:

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor that can provide sedation and analgesia with a rapid onset and short duration of action. However, analgesics should still be used for patients undergoing procedures that might cause visceral pain. Ketamine is contraindicated for patients with uncontrolled hypertension.

Dexmedetomidine is an alpha-2 agonist that can provide sedative and analgesic effects. It can cause procedural hypotension and bradycardia, so caution is advised in patients with cardiac disease and hepatic and/or renal insufficiencies.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or ketorolac, inhibit cyclooxygenase enzymes and can be considered in analgesic regimens. However, for most surgical procedures, the increased risk of bleeding due to platelet inhibition is a concern.

Continue to: Acetaminophen

Acetaminophen. Although its full mechanism of action has not been discovered, acetaminophen may also act on the cyclooxygenase pathway to produce analgesia. Compared with the oral formulation, IV acetaminophen is more expensive but may offer certain advantages, including faster plasma peak levels and lower production of acetaminophen’s toxic metabolite, N-acetyl-p-benzoquinone imine. Nonetheless, hepatotoxicity and overdose remain a concern.

The use of nonopioid analgesics during elective procedures that require pain control will allow continued use of an opioid antagonist such as naltrexone, while minimizing the risk for withdrawal or relapse. Their use must be evaluated on a case-by-case basis to ensure maximum safety and efficacy for each patient from both a medical and psychiatric standpoint. Overall, with the proper expertise and consultation, nonopioid pain regimens represent a reasonable alternative to opiates for patients who take naltrexone.

Related Resources

• American Society of Anesthesiologists. Standards guidelines and related resources. https://www.asahq.org/quality-and-practice-management/standards-guidelines-and-related-resources-search.
• American Society of Addiction Medicine. Clinical resources. https://www.asam.org/resources/guidelines-and-consensus-documents.

Drug Brand Names

Acetaminophen • Tylenol
Cetirizine • Zyrtec
Dexmedetomidine • Precedex
Ibuprofen • Caldolor (IV), Motrin (oral)
Ketamine • Ketalar
Ketorolac • Toradol
Lisinopril • Prinivil, Zestril
Naltrexone • ReVia, Vivitrol
Propofol • Diprivan
Simvastatin • Juvisync, Simcor

Mr. M, age 55, presents to his primary care physician (PCP) with hematochezia. Mr. M states that for the past week, he has noticed blood upon wiping after a bowel movement and is worried that he might have cancer.

Mr. M has a 10-year history of opioid use disorder as diagnosed by his psychiatrist. He is presently maintained on long-acting injectable naltrexone, 380 mg IM every 4 weeks, and has not used opioids for the past 1.5 years. Mr. M is also taking simvastatin, 40 mg, for dyslipidemia, lisinopril, 5 mg, for hypertension, and cetirizine, 5 mg as needed, for seasonal allergies.

A standard workup including a physical examination and laboratory tests are performed. Mr. M’s PCP would like for him to undergo a colonoscopy to investigate the etiology of the bleeding. In consultation with both the PCP and psychiatrist, the gastroenterologist determines that the colonoscopy can be performed within 48 hours with no changes to Mr. M’s medication regimen. The gastroenterologist utilizes a nonopioid, ketorolac, 30 mg IV, for pain management during the procedure. Diverticula were identified in the lower gastrointestinal tract and are treated endoscopically. Mr. M is successfully withdrawn from sedation with no adverse events or pain and continues to be in opioid remission.

Naltrexone competitively antagonizes opioid receptors with the highest affinity for the µ-opioid receptor. It is approved for treatment of alcohol and opioid dependence following opioid detoxification.¹ Its competitive inhibition at the µ-opioid receptor results in the inhibition of exogenous opioid effects. The medication is available as an orally administered tablet as well as a long-acting injection administered intramuscularly (Table 1¹). The long-acting injection can be useful in patients who have difficulty with adherence, because good adherence to naltrexone is required to maximize efficacy.

Due to its ability to block opioid analgesic effects, naltrexone presents a unique challenge for patients taking it who need to undergo procedures that require pain control. Pharmacologic regimens used during procedures often contain a sedative agent, such as propofol, and an opioid for analgesia. Alternative strategies are needed for patients taking naltrexone who require an opioid analgesic agent for procedures such as colonoscopies.

One strategy could be to withhold naltrexone before the procedure to ensure that the medication will not compete with the opioid agent to relieve pain. This strategy depends on the urgency of the procedure, the formulation of naltrexone being used, and patient-specific factors that may increase the risk for adverse events. For a non-urgent, elective procedure, it may be acceptable to hold oral naltrexone approximately 72 hours before the procedure. However, this is likely not a favorable approach for patients who may be at high risk for relapse or for patients who are receiving the long-acting formulation. Additionally, the use of an opioid agent intra- or post-operatively for pain may increase the risk of relapse. The use of opioids for such procedures may also be more difficult in a patient with a history of opioid abuse or dependence because he or she may have developed tolerance to opioids. Conversely, if a patient has been treated with naltrexone for an extended period, a lack of tolerance may increase the risk of respiratory depression with opioid administration due to upregulation of the opioid receptor.²

Continue to: Nonopioid analgesic agents

For a patient receiving naltrexone who needs to undergo a procedure, a multi­disciplinary consultation between the patient’s psychiatrist and other clinicians is key for providing a regimen that is safe and effective. A nonopioid analgesic agent may be considered to avoid the problematic interactions possible in these patients (Table 2^3-5). Nonopioid regimens can be utilized alone or in combination, and may include the following^3-5:

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor that can provide sedation and analgesia with a rapid onset and short duration of action. However, analgesics should still be used for patients undergoing procedures that might cause visceral pain. Ketamine is contraindicated for patients with uncontrolled hypertension.

Dexmedetomidine is an alpha-2 agonist that can provide sedative and analgesic effects. It can cause procedural hypotension and bradycardia, so caution is advised in patients with cardiac disease and hepatic and/or renal insufficiencies.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or ketorolac, inhibit cyclooxygenase enzymes and can be considered in analgesic regimens. However, for most surgical procedures, the increased risk of bleeding due to platelet inhibition is a concern.

Continue to: Acetaminophen

Acetaminophen. Although its full mechanism of action has not been discovered, acetaminophen may also act on the cyclooxygenase pathway to produce analgesia. Compared with the oral formulation, IV acetaminophen is more expensive but may offer certain advantages, including faster plasma peak levels and lower production of acetaminophen’s toxic metabolite, N-acetyl-p-benzoquinone imine. Nonetheless, hepatotoxicity and overdose remain a concern.

The use of nonopioid analgesics during elective procedures that require pain control will allow continued use of an opioid antagonist such as naltrexone, while minimizing the risk for withdrawal or relapse. Their use must be evaluated on a case-by-case basis to ensure maximum safety and efficacy for each patient from both a medical and psychiatric standpoint. Overall, with the proper expertise and consultation, nonopioid pain regimens represent a reasonable alternative to opiates for patients who take naltrexone.

Related Resources

• American Society of Anesthesiologists. Standards guidelines and related resources. https://www.asahq.org/quality-and-practice-management/standards-guidelines-and-related-resources-search.
• American Society of Addiction Medicine. Clinical resources. https://www.asam.org/resources/guidelines-and-consensus-documents.

Drug Brand Names

Acetaminophen • Tylenol
Cetirizine • Zyrtec
Dexmedetomidine • Precedex
Ibuprofen • Caldolor (IV), Motrin (oral)
Ketamine • Ketalar
Ketorolac • Toradol
Lisinopril • Prinivil, Zestril
Naltrexone • ReVia, Vivitrol
Propofol • Diprivan
Simvastatin • Juvisync, Simcor

Mr. M, age 55, presents to his primary care physician (PCP) with hematochezia. Mr. M states that for the past week, he has noticed blood upon wiping after a bowel movement and is worried that he might have cancer.

Mr. M has a 10-year history of opioid use disorder as diagnosed by his psychiatrist. He is presently maintained on long-acting injectable naltrexone, 380 mg IM every 4 weeks, and has not used opioids for the past 1.5 years. Mr. M is also taking simvastatin, 40 mg, for dyslipidemia, lisinopril, 5 mg, for hypertension, and cetirizine, 5 mg as needed, for seasonal allergies.

A standard workup including a physical examination and laboratory tests are performed. Mr. M’s PCP would like for him to undergo a colonoscopy to investigate the etiology of the bleeding. In consultation with both the PCP and psychiatrist, the gastroenterologist determines that the colonoscopy can be performed within 48 hours with no changes to Mr. M’s medication regimen. The gastroenterologist utilizes a nonopioid, ketorolac, 30 mg IV, for pain management during the procedure. Diverticula were identified in the lower gastrointestinal tract and are treated endoscopically. Mr. M is successfully withdrawn from sedation with no adverse events or pain and continues to be in opioid remission.

Naltrexone competitively antagonizes opioid receptors with the highest affinity for the µ-opioid receptor. It is approved for treatment of alcohol and opioid dependence following opioid detoxification.¹ Its competitive inhibition at the µ-opioid receptor results in the inhibition of exogenous opioid effects. The medication is available as an orally administered tablet as well as a long-acting injection administered intramuscularly (Table 1¹). The long-acting injection can be useful in patients who have difficulty with adherence, because good adherence to naltrexone is required to maximize efficacy.

Due to its ability to block opioid analgesic effects, naltrexone presents a unique challenge for patients taking it who need to undergo procedures that require pain control. Pharmacologic regimens used during procedures often contain a sedative agent, such as propofol, and an opioid for analgesia. Alternative strategies are needed for patients taking naltrexone who require an opioid analgesic agent for procedures such as colonoscopies.

One strategy could be to withhold naltrexone before the procedure to ensure that the medication will not compete with the opioid agent to relieve pain. This strategy depends on the urgency of the procedure, the formulation of naltrexone being used, and patient-specific factors that may increase the risk for adverse events. For a non-urgent, elective procedure, it may be acceptable to hold oral naltrexone approximately 72 hours before the procedure. However, this is likely not a favorable approach for patients who may be at high risk for relapse or for patients who are receiving the long-acting formulation. Additionally, the use of an opioid agent intra- or post-operatively for pain may increase the risk of relapse. The use of opioids for such procedures may also be more difficult in a patient with a history of opioid abuse or dependence because he or she may have developed tolerance to opioids. Conversely, if a patient has been treated with naltrexone for an extended period, a lack of tolerance may increase the risk of respiratory depression with opioid administration due to upregulation of the opioid receptor.²

Continue to: Nonopioid analgesic agents

For a patient receiving naltrexone who needs to undergo a procedure, a multi­disciplinary consultation between the patient’s psychiatrist and other clinicians is key for providing a regimen that is safe and effective. A nonopioid analgesic agent may be considered to avoid the problematic interactions possible in these patients (Table 2^3-5). Nonopioid regimens can be utilized alone or in combination, and may include the following^3-5:

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor that can provide sedation and analgesia with a rapid onset and short duration of action. However, analgesics should still be used for patients undergoing procedures that might cause visceral pain. Ketamine is contraindicated for patients with uncontrolled hypertension.

Dexmedetomidine is an alpha-2 agonist that can provide sedative and analgesic effects. It can cause procedural hypotension and bradycardia, so caution is advised in patients with cardiac disease and hepatic and/or renal insufficiencies.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or ketorolac, inhibit cyclooxygenase enzymes and can be considered in analgesic regimens. However, for most surgical procedures, the increased risk of bleeding due to platelet inhibition is a concern.

Continue to: Acetaminophen

Acetaminophen. Although its full mechanism of action has not been discovered, acetaminophen may also act on the cyclooxygenase pathway to produce analgesia. Compared with the oral formulation, IV acetaminophen is more expensive but may offer certain advantages, including faster plasma peak levels and lower production of acetaminophen’s toxic metabolite, N-acetyl-p-benzoquinone imine. Nonetheless, hepatotoxicity and overdose remain a concern.

The use of nonopioid analgesics during elective procedures that require pain control will allow continued use of an opioid antagonist such as naltrexone, while minimizing the risk for withdrawal or relapse. Their use must be evaluated on a case-by-case basis to ensure maximum safety and efficacy for each patient from both a medical and psychiatric standpoint. Overall, with the proper expertise and consultation, nonopioid pain regimens represent a reasonable alternative to opiates for patients who take naltrexone.

Related Resources

• American Society of Anesthesiologists. Standards guidelines and related resources. https://www.asahq.org/quality-and-practice-management/standards-guidelines-and-related-resources-search.
• American Society of Addiction Medicine. Clinical resources. https://www.asam.org/resources/guidelines-and-consensus-documents.

Drug Brand Names

Acetaminophen • Tylenol
Cetirizine • Zyrtec
Dexmedetomidine • Precedex
Ibuprofen • Caldolor (IV), Motrin (oral)
Ketamine • Ketalar
Ketorolac • Toradol
Lisinopril • Prinivil, Zestril
Naltrexone • ReVia, Vivitrol
Propofol • Diprivan
Simvastatin • Juvisync, Simcor

Psychiatry is a field of passion. The reward of experiencing growth and change alongside our patients is what bolsters us through years of difficult training, overnight shifts, endless paperwork, regulatory mandates, and frequent worry about our patients. As physicians, we don’t live for weekends as many other professionals do. To the contrary, we spend them on call, moonlighting, laboring over journal articles, and perfecting lectures.

That passion is what makes us trusted clinicians and experts in our field. It can also make it difficult for us to disconnect from our work, frequently leading to burnout. Physician self-care, support, and professional development are critical topics that modern-day medicine minimizes at the peril of physicians and public health.¹

Psychiatry lends itself to a deep and intimate understanding of another human being. The therapist delves into the lives of his or her patients, hears their stories, and holds their secrets. In some cases, we might be the only ones who truly see patients for who they uniquely are, and come to understand them on a deeper level than their closest family and friends. This can be both thrilling and intense. As we delve into the psyche of another individual, contemplate which interpretation we should share, and resonate with our patients, it is easy to become bogged down with our own countertransference, sentiment, and worry, and to become consumed by our work. A professional hazard, some might quip.

Therefore, personal restoration—a tool that keeps our clinical skills sharp—is vitally important to caring for oneself and one’s patient. Surprisingly, this can be neglected until we begin to experience burnout, which over time could transform into impairment, thus endangering ourselves, our patients, and our profession.

Over the past decade, physician impairment has been exhaustively described, researched, and addressed. However, most analyses have focused on identifying impairment, and offering guidance on how to properly report it. How do we shift from managing the crisis to preventing it? To answer this question, this article:

• reviews the dilemma of physician impairment
• explores the duty we have to patients, ourselves, and the profession
• discusses shifting the focus on impairment to prevention through well-being.

Continue to: Dilemma

The cornerstone for well-being is a balanced life. No matter how much one loves his or her work, there must be balance between work, relationships, and hobbies. Without that equilibrium, everyone is put at risk.²

Just as our patients, we are not immune to mental illness, cognitive decline, or substance abuse.³ We might even be more susceptible. For many physicians, their identity is intimately tied to their work.⁴ Dr. Robin Weiss captured that intimate relationship⁵:

“… [A] therapist may spend hundreds of hours, perhaps more than a thousand, hearing about a patient’s most exalted aspirations and most murderous, hateful fantasies. During this time, the patient may endure excruciating losses, unbearable shame, bitter sadness and great triumphs. You may accompany patients through torturous adolescence into adulthood. Or you may meet them in middle age and be with them as they age and eventually die. You collaborate in a deep process of discovery. Few encounters are this deeply honest, and therefore intimate.”

Given the stories we hear and the resulting intimacy and countertransference that inevitably arise, psychiatrists are even more prone to burnout than other physicians.⁶ Physician impairment is a public health issue that affects not just physicians but also their families, colleagues, and patients.

“Impairment” for the purpose of this article means a physical, mental, or substance-related disorder that interferes with a physician’s ability to undertake professional activities competently and safely.⁷ Predisposing factors for physician impairment include an obsessive-compulsive personality type, a family history of mental illness, sensation-seeking behavior, denial of personal problems, perfectionism, and idealism.^8,9 Also, work stress becomes a significant factor in already vulnerable physicians, leading to a greater risk for mental illness.¹⁰

Continue to: Some warning signs of impairment include...

Duty: To ourselves, our colleagues, and our patients

There has been much discussion on how to report impaired colleagues, but little on how to help and support ourselves and our colleagues before things escalate into serious problems. And this lack of discussion is at the detriment of individual practitioners, their families, and patients. Physicians-in-training, including psychiatric residents, are at particularly high risk for developing stress-related problems, depression, and substance misuse.¹² Occupational demands, self-criticism, and denial of one’s distress are common among physicians, as is self-treatment with drugs and alcohol.¹³

We all know by now that doctors and physician health programs (PHPs) have a duty to report impaired colleagues who continue to practice despite reasonable offers of assistance. There are an abundance of PHPs that are in place to assist with such situations. The American Medical Association’s official position on reporting impairment is outlined in Policy H-275.952.⁷ There also is the Federation of State Medical Boards. Its policy states that PHPs have “a primary commitment to [help] state medical boards … protect the public … [These] programs [should] demonstrate an ongoing track of record of ensuring safety to the public and reveal deficiencies if they occur.”¹⁴

Legal and ethical issues, however, complicate interventions for colleagues who need assistance.¹⁵ Despite the existence of PHPs, it would be much easier—not to mention helpful—to help a colleague by carrying out early interventions.

Discussion: Prevention as a solution

More emphasis should be placed on prevention. That’s where self-care and well-being come into play. Awareness of and sensitivity to physician vulnerability, early detection, and prevention of impairment are important.

Continue to: There has been a paradigm shift in focus...

There has been a paradigm shift in focus across medical boards, professional societies, and medical colleges. They are recognizing that personal well-being can help prevent burnout and, in turn, change the landscape of medicine from endless work to balanced lives that yield more satisfying and joyful work. It is becoming an accepted fact in medicine that well-being is just as important as integrity, professionalism, and patient safety. For example, the American Academy of Medical Colleges (AAMC) issued a statement emphasizing the importance of clinician well-being and dedicated its June 2016 Leadership Forum to a range of topics addressing depression, resilience, burnout, and suicide in academic medicine.¹⁶

Anita Everett, MD, put the spotlight on physician well-being during her term as American Psychiatric Association President (2017 to 2018). She formed a specific workgroup on Physician Wellness and Burnout where there is a community focus on prevention and self-care.¹⁷ A strong sense of community and purpose is almost always part of the prescription for promoting greater well-being.²

The importance of this issue is also trickling down from policymakers into hospitals and community health centers. Consider an initiative at Minneapolis’s Hennepin County Medical Center. Leaders there created a “reset room” for physicians to quietly decompress. The room is complete with LED lights, flameless candles, a sound machine, comfortable chairs, several plants, and an “in use” sign on the door.¹⁸ Other personal strategies to help prevent burnout include making environmental changes, encouraging hobbies, and streamlining burdensome tasks such as paperwork and electronic medical record systems.

As physician health and well-being are finally emerging as a “hot topic,”² educational and treatment resources are increasingly available for any of us to explore. Consider a simple Google search to look into your State’s PHPs, and get involved in your professional societies to make change.

The culture is starting to shift, and leading by example will be a key to propelling further progress in this area. Model our own self-care for colleagues and patients alike. As Mark Twain said, we might love our work, but we must remember that being solely defined by work comes to the detriment of our health. Maintaining balance is what will allow us to sustain long careers ahead doing what we love.

Psychiatry is a field of passion. The reward of experiencing growth and change alongside our patients is what bolsters us through years of difficult training, overnight shifts, endless paperwork, regulatory mandates, and frequent worry about our patients. As physicians, we don’t live for weekends as many other professionals do. To the contrary, we spend them on call, moonlighting, laboring over journal articles, and perfecting lectures.

That passion is what makes us trusted clinicians and experts in our field. It can also make it difficult for us to disconnect from our work, frequently leading to burnout. Physician self-care, support, and professional development are critical topics that modern-day medicine minimizes at the peril of physicians and public health.¹

Psychiatry lends itself to a deep and intimate understanding of another human being. The therapist delves into the lives of his or her patients, hears their stories, and holds their secrets. In some cases, we might be the only ones who truly see patients for who they uniquely are, and come to understand them on a deeper level than their closest family and friends. This can be both thrilling and intense. As we delve into the psyche of another individual, contemplate which interpretation we should share, and resonate with our patients, it is easy to become bogged down with our own countertransference, sentiment, and worry, and to become consumed by our work. A professional hazard, some might quip.

Therefore, personal restoration—a tool that keeps our clinical skills sharp—is vitally important to caring for oneself and one’s patient. Surprisingly, this can be neglected until we begin to experience burnout, which over time could transform into impairment, thus endangering ourselves, our patients, and our profession.

Over the past decade, physician impairment has been exhaustively described, researched, and addressed. However, most analyses have focused on identifying impairment, and offering guidance on how to properly report it. How do we shift from managing the crisis to preventing it? To answer this question, this article:

• reviews the dilemma of physician impairment
• explores the duty we have to patients, ourselves, and the profession
• discusses shifting the focus on impairment to prevention through well-being.

Continue to: Dilemma

The cornerstone for well-being is a balanced life. No matter how much one loves his or her work, there must be balance between work, relationships, and hobbies. Without that equilibrium, everyone is put at risk.²

Just as our patients, we are not immune to mental illness, cognitive decline, or substance abuse.³ We might even be more susceptible. For many physicians, their identity is intimately tied to their work.⁴ Dr. Robin Weiss captured that intimate relationship⁵:

“… [A] therapist may spend hundreds of hours, perhaps more than a thousand, hearing about a patient’s most exalted aspirations and most murderous, hateful fantasies. During this time, the patient may endure excruciating losses, unbearable shame, bitter sadness and great triumphs. You may accompany patients through torturous adolescence into adulthood. Or you may meet them in middle age and be with them as they age and eventually die. You collaborate in a deep process of discovery. Few encounters are this deeply honest, and therefore intimate.”

Given the stories we hear and the resulting intimacy and countertransference that inevitably arise, psychiatrists are even more prone to burnout than other physicians.⁶ Physician impairment is a public health issue that affects not just physicians but also their families, colleagues, and patients.

“Impairment” for the purpose of this article means a physical, mental, or substance-related disorder that interferes with a physician’s ability to undertake professional activities competently and safely.⁷ Predisposing factors for physician impairment include an obsessive-compulsive personality type, a family history of mental illness, sensation-seeking behavior, denial of personal problems, perfectionism, and idealism.^8,9 Also, work stress becomes a significant factor in already vulnerable physicians, leading to a greater risk for mental illness.¹⁰

Continue to: Some warning signs of impairment include...

Duty: To ourselves, our colleagues, and our patients

There has been much discussion on how to report impaired colleagues, but little on how to help and support ourselves and our colleagues before things escalate into serious problems. And this lack of discussion is at the detriment of individual practitioners, their families, and patients. Physicians-in-training, including psychiatric residents, are at particularly high risk for developing stress-related problems, depression, and substance misuse.¹² Occupational demands, self-criticism, and denial of one’s distress are common among physicians, as is self-treatment with drugs and alcohol.¹³

We all know by now that doctors and physician health programs (PHPs) have a duty to report impaired colleagues who continue to practice despite reasonable offers of assistance. There are an abundance of PHPs that are in place to assist with such situations. The American Medical Association’s official position on reporting impairment is outlined in Policy H-275.952.⁷ There also is the Federation of State Medical Boards. Its policy states that PHPs have “a primary commitment to [help] state medical boards … protect the public … [These] programs [should] demonstrate an ongoing track of record of ensuring safety to the public and reveal deficiencies if they occur.”¹⁴

Legal and ethical issues, however, complicate interventions for colleagues who need assistance.¹⁵ Despite the existence of PHPs, it would be much easier—not to mention helpful—to help a colleague by carrying out early interventions.

Discussion: Prevention as a solution

More emphasis should be placed on prevention. That’s where self-care and well-being come into play. Awareness of and sensitivity to physician vulnerability, early detection, and prevention of impairment are important.

Continue to: There has been a paradigm shift in focus...

There has been a paradigm shift in focus across medical boards, professional societies, and medical colleges. They are recognizing that personal well-being can help prevent burnout and, in turn, change the landscape of medicine from endless work to balanced lives that yield more satisfying and joyful work. It is becoming an accepted fact in medicine that well-being is just as important as integrity, professionalism, and patient safety. For example, the American Academy of Medical Colleges (AAMC) issued a statement emphasizing the importance of clinician well-being and dedicated its June 2016 Leadership Forum to a range of topics addressing depression, resilience, burnout, and suicide in academic medicine.¹⁶

Anita Everett, MD, put the spotlight on physician well-being during her term as American Psychiatric Association President (2017 to 2018). She formed a specific workgroup on Physician Wellness and Burnout where there is a community focus on prevention and self-care.¹⁷ A strong sense of community and purpose is almost always part of the prescription for promoting greater well-being.²

The importance of this issue is also trickling down from policymakers into hospitals and community health centers. Consider an initiative at Minneapolis’s Hennepin County Medical Center. Leaders there created a “reset room” for physicians to quietly decompress. The room is complete with LED lights, flameless candles, a sound machine, comfortable chairs, several plants, and an “in use” sign on the door.¹⁸ Other personal strategies to help prevent burnout include making environmental changes, encouraging hobbies, and streamlining burdensome tasks such as paperwork and electronic medical record systems.

As physician health and well-being are finally emerging as a “hot topic,”² educational and treatment resources are increasingly available for any of us to explore. Consider a simple Google search to look into your State’s PHPs, and get involved in your professional societies to make change.

The culture is starting to shift, and leading by example will be a key to propelling further progress in this area. Model our own self-care for colleagues and patients alike. As Mark Twain said, we might love our work, but we must remember that being solely defined by work comes to the detriment of our health. Maintaining balance is what will allow us to sustain long careers ahead doing what we love.

Psychiatry is a field of passion. The reward of experiencing growth and change alongside our patients is what bolsters us through years of difficult training, overnight shifts, endless paperwork, regulatory mandates, and frequent worry about our patients. As physicians, we don’t live for weekends as many other professionals do. To the contrary, we spend them on call, moonlighting, laboring over journal articles, and perfecting lectures.

That passion is what makes us trusted clinicians and experts in our field. It can also make it difficult for us to disconnect from our work, frequently leading to burnout. Physician self-care, support, and professional development are critical topics that modern-day medicine minimizes at the peril of physicians and public health.¹

Psychiatry lends itself to a deep and intimate understanding of another human being. The therapist delves into the lives of his or her patients, hears their stories, and holds their secrets. In some cases, we might be the only ones who truly see patients for who they uniquely are, and come to understand them on a deeper level than their closest family and friends. This can be both thrilling and intense. As we delve into the psyche of another individual, contemplate which interpretation we should share, and resonate with our patients, it is easy to become bogged down with our own countertransference, sentiment, and worry, and to become consumed by our work. A professional hazard, some might quip.

Therefore, personal restoration—a tool that keeps our clinical skills sharp—is vitally important to caring for oneself and one’s patient. Surprisingly, this can be neglected until we begin to experience burnout, which over time could transform into impairment, thus endangering ourselves, our patients, and our profession.

Over the past decade, physician impairment has been exhaustively described, researched, and addressed. However, most analyses have focused on identifying impairment, and offering guidance on how to properly report it. How do we shift from managing the crisis to preventing it? To answer this question, this article:

• reviews the dilemma of physician impairment
• explores the duty we have to patients, ourselves, and the profession
• discusses shifting the focus on impairment to prevention through well-being.

Continue to: Dilemma

The cornerstone for well-being is a balanced life. No matter how much one loves his or her work, there must be balance between work, relationships, and hobbies. Without that equilibrium, everyone is put at risk.²

Just as our patients, we are not immune to mental illness, cognitive decline, or substance abuse.³ We might even be more susceptible. For many physicians, their identity is intimately tied to their work.⁴ Dr. Robin Weiss captured that intimate relationship⁵:

“… [A] therapist may spend hundreds of hours, perhaps more than a thousand, hearing about a patient’s most exalted aspirations and most murderous, hateful fantasies. During this time, the patient may endure excruciating losses, unbearable shame, bitter sadness and great triumphs. You may accompany patients through torturous adolescence into adulthood. Or you may meet them in middle age and be with them as they age and eventually die. You collaborate in a deep process of discovery. Few encounters are this deeply honest, and therefore intimate.”

Given the stories we hear and the resulting intimacy and countertransference that inevitably arise, psychiatrists are even more prone to burnout than other physicians.⁶ Physician impairment is a public health issue that affects not just physicians but also their families, colleagues, and patients.

“Impairment” for the purpose of this article means a physical, mental, or substance-related disorder that interferes with a physician’s ability to undertake professional activities competently and safely.⁷ Predisposing factors for physician impairment include an obsessive-compulsive personality type, a family history of mental illness, sensation-seeking behavior, denial of personal problems, perfectionism, and idealism.^8,9 Also, work stress becomes a significant factor in already vulnerable physicians, leading to a greater risk for mental illness.¹⁰

Continue to: Some warning signs of impairment include...

Duty: To ourselves, our colleagues, and our patients

There has been much discussion on how to report impaired colleagues, but little on how to help and support ourselves and our colleagues before things escalate into serious problems. And this lack of discussion is at the detriment of individual practitioners, their families, and patients. Physicians-in-training, including psychiatric residents, are at particularly high risk for developing stress-related problems, depression, and substance misuse.¹² Occupational demands, self-criticism, and denial of one’s distress are common among physicians, as is self-treatment with drugs and alcohol.¹³

We all know by now that doctors and physician health programs (PHPs) have a duty to report impaired colleagues who continue to practice despite reasonable offers of assistance. There are an abundance of PHPs that are in place to assist with such situations. The American Medical Association’s official position on reporting impairment is outlined in Policy H-275.952.⁷ There also is the Federation of State Medical Boards. Its policy states that PHPs have “a primary commitment to [help] state medical boards … protect the public … [These] programs [should] demonstrate an ongoing track of record of ensuring safety to the public and reveal deficiencies if they occur.”¹⁴

Legal and ethical issues, however, complicate interventions for colleagues who need assistance.¹⁵ Despite the existence of PHPs, it would be much easier—not to mention helpful—to help a colleague by carrying out early interventions.

Discussion: Prevention as a solution

More emphasis should be placed on prevention. That’s where self-care and well-being come into play. Awareness of and sensitivity to physician vulnerability, early detection, and prevention of impairment are important.

Continue to: There has been a paradigm shift in focus...

There has been a paradigm shift in focus across medical boards, professional societies, and medical colleges. They are recognizing that personal well-being can help prevent burnout and, in turn, change the landscape of medicine from endless work to balanced lives that yield more satisfying and joyful work. It is becoming an accepted fact in medicine that well-being is just as important as integrity, professionalism, and patient safety. For example, the American Academy of Medical Colleges (AAMC) issued a statement emphasizing the importance of clinician well-being and dedicated its June 2016 Leadership Forum to a range of topics addressing depression, resilience, burnout, and suicide in academic medicine.¹⁶

Anita Everett, MD, put the spotlight on physician well-being during her term as American Psychiatric Association President (2017 to 2018). She formed a specific workgroup on Physician Wellness and Burnout where there is a community focus on prevention and self-care.¹⁷ A strong sense of community and purpose is almost always part of the prescription for promoting greater well-being.²

The importance of this issue is also trickling down from policymakers into hospitals and community health centers. Consider an initiative at Minneapolis’s Hennepin County Medical Center. Leaders there created a “reset room” for physicians to quietly decompress. The room is complete with LED lights, flameless candles, a sound machine, comfortable chairs, several plants, and an “in use” sign on the door.¹⁸ Other personal strategies to help prevent burnout include making environmental changes, encouraging hobbies, and streamlining burdensome tasks such as paperwork and electronic medical record systems.

As physician health and well-being are finally emerging as a “hot topic,”² educational and treatment resources are increasingly available for any of us to explore. Consider a simple Google search to look into your State’s PHPs, and get involved in your professional societies to make change.

The culture is starting to shift, and leading by example will be a key to propelling further progress in this area. Model our own self-care for colleagues and patients alike. As Mark Twain said, we might love our work, but we must remember that being solely defined by work comes to the detriment of our health. Maintaining balance is what will allow us to sustain long careers ahead doing what we love.

CHICAGO – Consider 24-hour ambulatory blood pressure monitoring when patients complain about not getting enough sleep. You might catch hypertension early, according to researchers from the University of Pennsylvania, Philadelphia, and elsewhere.

M. Alexander Otto/MDedge News

They found a strong association between elevated 24-hour systolic blood pressure and short sleep duration, less than 7 hours a night and a mean in the study of 5.5 hours. Every 2-2.5 minutes of lost sleep was associated with an increase of 1 mm Hg in 24-hour mean systolic blood pressure and a increase of 1 beat per minute in heart rate.

The relationship was independent of office BP, nocturnal dipping status, and BP variability. It held in both the obese and nonobese, and in patients with and without obstructive sleep apnea (OSA). However, the relationship was found only among subjects who were not on antihypertensive medications.

“Adults with shorter sleep duration may benefit from screening with 24-hour ambulatory BP monitoring to promote earlier detection of hypertension and potentially mitigate the” the risk of cardiovascular disease. “This may be particularly important in screening for masked hypertension,” meaning normal pressures in the office, but elevated pressures at home, said investigators led by Jordana Cohen, MD, of the department of medicine at the University of Pennsylvania in a presentation at the joint scientific sessions of AHA Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

Dr. Cohen suggested that perhaps the sympathetic and endothelial derangements that drive hypertension in OSA also affect people with insufficient sleep. It may be that the normal morning surge in blood pressure persists longer into the day, she suggested. The investigative team analyzed data from two studies. The first, LIMBS (Lifestyle Modification in BP Lowering Study), was a phase 2 trial assessing yoga for blood pressure lowering. It was conducted in West Philadelphia and excluded people with diabetes, hypertension, OSA, and kidney or cardiovascular disease. The new analysis included 66 LIMBS subjects who had 24-hour blood pressure monitoring and kept sleep diaries to record their sleep duration (J Clin Hypertens (Greenwich). 2016 Aug;18[8]:809-16).

The team also analyzed 153 subjects from the PISA (Penn Icelandic Sleep Apnea) cohort, an ongoing project assessing continuous positive airway pressure for OSA, among other things. PISA includes patients with OSA, diabetes, hypertension, and kidney or cardiovascular disease. Sleep duration in the 153 subjects was again self-reported, but corroborated by actigraphy (J Sleep Res. 2015 Jun;24[3]:328-38).

The new findings were driven mostly by higher daytime systolic BP among short sleepers in LIMBS, and higher systolic pressures during both day and night among short sleepers in PISA, compared with subjects who slept at least 7 hours, and a mean of 8.5 hours, with napping included in overall sleep duration assessment.

In LIMBS, the mean 24-hour systolic BP was 12.7 mm Hg higher and the average heart rate 8 bpm faster among short sleepers; in PISA, the mean 24-hour systolic BP was 4.7 mm Hg higher and the heart rate 2 bpm faster.

Every 2.57 minutes of sleep lost in LIMBS and every 1.99 minute of lost sleep in PISA was associated with a 1–mm Hg gain in mean systolic BP and about a 1-bpm increase in heart rate. The findings were statistically significant and adjusted for age, race, body mass index, nocturnal dipping status, and office systolic blood pressure.

Baseline characteristics were generally well matched between short and long sleepers in both studies. However, while mean office systolic BP in LIMBS was the same in both sleep groups at about 139 mm Hg, the mean office systolic BP among long sleepers in PISA was 130 mm Hg versus 136 mm Hg among short sleepers, a significant difference.

It’s unclear why some people slept less, Dr. Cohen said, and the use of sleeping pills wasn’t considered in the analysis. Patients were an average of about 50 years old, with a body mass index of about 30 mg/m². The same model of 24-hour blood pressure monitor was used in both studies.

The work was funded by the National Institutes of Health. The investigators had no disclosures.
 

CHICAGO – Consider 24-hour ambulatory blood pressure monitoring when patients complain about not getting enough sleep. You might catch hypertension early, according to researchers from the University of Pennsylvania, Philadelphia, and elsewhere.

M. Alexander Otto/MDedge News

They found a strong association between elevated 24-hour systolic blood pressure and short sleep duration, less than 7 hours a night and a mean in the study of 5.5 hours. Every 2-2.5 minutes of lost sleep was associated with an increase of 1 mm Hg in 24-hour mean systolic blood pressure and a increase of 1 beat per minute in heart rate.

The relationship was independent of office BP, nocturnal dipping status, and BP variability. It held in both the obese and nonobese, and in patients with and without obstructive sleep apnea (OSA). However, the relationship was found only among subjects who were not on antihypertensive medications.

“Adults with shorter sleep duration may benefit from screening with 24-hour ambulatory BP monitoring to promote earlier detection of hypertension and potentially mitigate the” the risk of cardiovascular disease. “This may be particularly important in screening for masked hypertension,” meaning normal pressures in the office, but elevated pressures at home, said investigators led by Jordana Cohen, MD, of the department of medicine at the University of Pennsylvania in a presentation at the joint scientific sessions of AHA Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

Dr. Cohen suggested that perhaps the sympathetic and endothelial derangements that drive hypertension in OSA also affect people with insufficient sleep. It may be that the normal morning surge in blood pressure persists longer into the day, she suggested. The investigative team analyzed data from two studies. The first, LIMBS (Lifestyle Modification in BP Lowering Study), was a phase 2 trial assessing yoga for blood pressure lowering. It was conducted in West Philadelphia and excluded people with diabetes, hypertension, OSA, and kidney or cardiovascular disease. The new analysis included 66 LIMBS subjects who had 24-hour blood pressure monitoring and kept sleep diaries to record their sleep duration (J Clin Hypertens (Greenwich). 2016 Aug;18[8]:809-16).

The team also analyzed 153 subjects from the PISA (Penn Icelandic Sleep Apnea) cohort, an ongoing project assessing continuous positive airway pressure for OSA, among other things. PISA includes patients with OSA, diabetes, hypertension, and kidney or cardiovascular disease. Sleep duration in the 153 subjects was again self-reported, but corroborated by actigraphy (J Sleep Res. 2015 Jun;24[3]:328-38).

The new findings were driven mostly by higher daytime systolic BP among short sleepers in LIMBS, and higher systolic pressures during both day and night among short sleepers in PISA, compared with subjects who slept at least 7 hours, and a mean of 8.5 hours, with napping included in overall sleep duration assessment.

In LIMBS, the mean 24-hour systolic BP was 12.7 mm Hg higher and the average heart rate 8 bpm faster among short sleepers; in PISA, the mean 24-hour systolic BP was 4.7 mm Hg higher and the heart rate 2 bpm faster.

Every 2.57 minutes of sleep lost in LIMBS and every 1.99 minute of lost sleep in PISA was associated with a 1–mm Hg gain in mean systolic BP and about a 1-bpm increase in heart rate. The findings were statistically significant and adjusted for age, race, body mass index, nocturnal dipping status, and office systolic blood pressure.

Baseline characteristics were generally well matched between short and long sleepers in both studies. However, while mean office systolic BP in LIMBS was the same in both sleep groups at about 139 mm Hg, the mean office systolic BP among long sleepers in PISA was 130 mm Hg versus 136 mm Hg among short sleepers, a significant difference.

It’s unclear why some people slept less, Dr. Cohen said, and the use of sleeping pills wasn’t considered in the analysis. Patients were an average of about 50 years old, with a body mass index of about 30 mg/m². The same model of 24-hour blood pressure monitor was used in both studies.

The work was funded by the National Institutes of Health. The investigators had no disclosures.
 

CHICAGO – Consider 24-hour ambulatory blood pressure monitoring when patients complain about not getting enough sleep. You might catch hypertension early, according to researchers from the University of Pennsylvania, Philadelphia, and elsewhere.

M. Alexander Otto/MDedge News

They found a strong association between elevated 24-hour systolic blood pressure and short sleep duration, less than 7 hours a night and a mean in the study of 5.5 hours. Every 2-2.5 minutes of lost sleep was associated with an increase of 1 mm Hg in 24-hour mean systolic blood pressure and a increase of 1 beat per minute in heart rate.

The relationship was independent of office BP, nocturnal dipping status, and BP variability. It held in both the obese and nonobese, and in patients with and without obstructive sleep apnea (OSA). However, the relationship was found only among subjects who were not on antihypertensive medications.

“Adults with shorter sleep duration may benefit from screening with 24-hour ambulatory BP monitoring to promote earlier detection of hypertension and potentially mitigate the” the risk of cardiovascular disease. “This may be particularly important in screening for masked hypertension,” meaning normal pressures in the office, but elevated pressures at home, said investigators led by Jordana Cohen, MD, of the department of medicine at the University of Pennsylvania in a presentation at the joint scientific sessions of AHA Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

Dr. Cohen suggested that perhaps the sympathetic and endothelial derangements that drive hypertension in OSA also affect people with insufficient sleep. It may be that the normal morning surge in blood pressure persists longer into the day, she suggested. The investigative team analyzed data from two studies. The first, LIMBS (Lifestyle Modification in BP Lowering Study), was a phase 2 trial assessing yoga for blood pressure lowering. It was conducted in West Philadelphia and excluded people with diabetes, hypertension, OSA, and kidney or cardiovascular disease. The new analysis included 66 LIMBS subjects who had 24-hour blood pressure monitoring and kept sleep diaries to record their sleep duration (J Clin Hypertens (Greenwich). 2016 Aug;18[8]:809-16).

The team also analyzed 153 subjects from the PISA (Penn Icelandic Sleep Apnea) cohort, an ongoing project assessing continuous positive airway pressure for OSA, among other things. PISA includes patients with OSA, diabetes, hypertension, and kidney or cardiovascular disease. Sleep duration in the 153 subjects was again self-reported, but corroborated by actigraphy (J Sleep Res. 2015 Jun;24[3]:328-38).

The new findings were driven mostly by higher daytime systolic BP among short sleepers in LIMBS, and higher systolic pressures during both day and night among short sleepers in PISA, compared with subjects who slept at least 7 hours, and a mean of 8.5 hours, with napping included in overall sleep duration assessment.

In LIMBS, the mean 24-hour systolic BP was 12.7 mm Hg higher and the average heart rate 8 bpm faster among short sleepers; in PISA, the mean 24-hour systolic BP was 4.7 mm Hg higher and the heart rate 2 bpm faster.

Every 2.57 minutes of sleep lost in LIMBS and every 1.99 minute of lost sleep in PISA was associated with a 1–mm Hg gain in mean systolic BP and about a 1-bpm increase in heart rate. The findings were statistically significant and adjusted for age, race, body mass index, nocturnal dipping status, and office systolic blood pressure.

Baseline characteristics were generally well matched between short and long sleepers in both studies. However, while mean office systolic BP in LIMBS was the same in both sleep groups at about 139 mm Hg, the mean office systolic BP among long sleepers in PISA was 130 mm Hg versus 136 mm Hg among short sleepers, a significant difference.

It’s unclear why some people slept less, Dr. Cohen said, and the use of sleeping pills wasn’t considered in the analysis. Patients were an average of about 50 years old, with a body mass index of about 30 mg/m². The same model of 24-hour blood pressure monitor was used in both studies.

The work was funded by the National Institutes of Health. The investigators had no disclosures.