Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

[polldaddy:9903171]

The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

[polldaddy:9903172]

Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

[polldaddy:9903171]

The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

[polldaddy:9903172]

Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

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The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

[polldaddy:9903172]

Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

In Dr. Mary Moller’s Guest Editorial “Advancing the role of advanced practice psychiatric nurses in today’s psychiatric workforce” (Current Psychiatry. April 2017, p. 15-16,18-20), she asserts that the American Psychiatric Association (APA) should take a stand against the American Medical Association (AMA) because AMA lobbyists pose a barrier to allowing advanced practice registered nurses (APRNs) to engage in autonomous practice. She argues that physician supervision is nothing more than a means of earning extra money for some physicians, calling it a “cottage industry.” Although she states that psychiatric APRNs provide skilled psychiatric care from a “nursing perspective” and argues that we “come together to respect our given scopes of practice,” the implication is clear: “to remove unnecessary barriers to practice and promote a unified and collegial workforce” is to assert that APRNs can do anything psychiatrists do. As physicians, we all know this is not the case. To support autonomous practice is to promote a reckless endeavor that endangers our patients.

Dr. Moller cited a source from the Federal Trade Commission¹ that encourages the autonomous practice of APRNs to increase competition. This again implies the false equivalency between physicians and APRNs. Competition implies that the players are providing the same service. If, as nurse practitioners argue, they practice “nursing,” then they are not practicing “medicine.” Physicians and APRNs do not have the same background. Although both are charged with the care of patients, nursing is not medicine, nor should it be. Both are important and needed, but nursing was never designed to be an autonomous practice. According to the American Association of Colleges of Nursing, “Nursing and medicine are distinct health disciplines that prepare clinicians to assume different roles and meet different practice expectations.”² In fact, the curriculum and requirements to become an APRN vary depending on the program, and some programs do not even require a BSN.³ There are online programs available for earning an APRN degree. Additionally, APRNs are only required to have 500 to 700 total hours of patient care,⁴ compared with the >10,000 hours physicians have once they have finished a 3-year residency, which when combined with their education amounts to >20,000 hours.⁵ This doesn’t account for those who have longer residencies or fellowships to further specialize in their area of training.

Dr. Moller’s main argument is that there is a dire shortage of psychiatrists and that the only way to meet this need for more providers is to make APRNs autonomous. However, no data indicate that autonomous practice of mid-level providers leads to an influx of these providers in rural areas, where the need would be greatest. Although current data on this are quite sparse, some studies indicate that the majority practice in urban areas, even in states with independent practice authority.^6,7 Dr. Moller cites a source that only reviewed home zip codes of psychiatric APRNs but did not include zip codes of employment.⁸ Only 13% of psychiatric APRNs live in rural areas across the United States. Therefore, it is a false assertion to state that these APRNs are found primarily in rural and less populated urban areas. It is also false to imply and assume that these APRNs practice in the rural areas.

In 2017, there were 43,157 registered physician applications, with 35,969 active applications for 31,757 residency positions in the United States, and at least 11,400 medical school graduates were unmatched.⁹ Imagine how much more we could serve our patients by matching these graduates, whose training far surpasses that of a mid-level provider. The Resident Physician Shortage Reduction Act of 2017 aims to address this problem by increasing Medicare-funded graduate medical education (GME) residency programs in the United States.¹⁰ We can make a difference by contacting our members of Congress to encourage them to support this bill. In addition, the AMA is advocating to save funding for GME and provides an easy-to-use Web site (https://savegme.org/take-action) to contact your legislators directly to show your support for GME.

Nurse practitioners have tremendous value when their role is a part of a team; however, they should not practice without supervision, and physicians who supervise them absolutely should be providing adequate super­vision. I applaud the APA and the AMA for standing up for the practice of medicine and for our patients. I hope that they continue to do so, and I encourage them to increase their efforts.

Laura Kendall, MD
Assistant Professor of Clinical Psychiatry
Department of Psychiatry and Behavioral Sciences
Keck School of Medicine
University of Southern California
Los Angeles, California

References
1. Koslov T; Office of Policy Planning. The doctor (or nurse practitioner) will see you now: competition and the regulation of advanced practice nurses. Federal Trade Commission. https://www.ftc.gov/news-events/blogs/competition-matters/2014/03/doctor-or-nurse-practitioner-will-see-you-now. Published March 7, 2014. Accessed July 26, 2017.
2. American Association of Colleges of Nursing. DNP talking points. http://www.aacnnursing.org/DNP/about/talking-points. Updated July, 2014. Accessed August 12, 2017.
3. Keyes L. MSN without a BSN? MastersInNursing.com. https://www.mastersinnursing.com/msn-without-a-bsn. Accessed August 12, 2017.
4. Iglehart JK. Expanding the role of advanced nurse practitioners—risks and rewards. New Engl J Med. 2013;368(20):1935-1941.
5. Primary Care Coalition. Issue brief: collaboration between physicians and nurses works. Compare the education gaps between primary care physicians and nurse practitioners. http://www.tafp.org/Media/Default/Downloads/advocacy/scope-education.pdf. Published November 1, 2010. Accessed October 11, 2017.
6. American Medical Association. Issue brief: independent nursing practice. https://www.ama-assn.org/system/files/media-browser/premium/arc/ama-issue-brief-independent-nursing-practice.pdf. Updated 2017.
7. Tabor J, Jennings N, Kohler L, et al. The supply of physician assistants, nurse practitioners, and certified nurse midwives in Arizona. University of Arizona. http://azahec.uahs.arizona.edu/sites/default/files/u9/supply_of_pa_np_cnm.pdf. Accessed October 11, 2017.
8. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.
9. 2017 NRMP Main Residency Match the largest match on record [press release]. Washington, DC: National Resident Matching Program; March 17, 2017. http://www.nrmp.org/press-release-2017-nrmp-main-residency-match-the-largest-match-on-record. Accessed October 11, 2017.
10. Resident Physician Shortage Reduction Act of 2017, HR 2267, 115th Cong, 1st session (2017).

The author responds

I would like to thank Dr. Kendall for her passionate letter about my editorial and provide the following response. I neither asserted the equivalency of doctors and nurses or that APRNs can do what MDs do. Rather, APRNs are educated to provide highly qualified, specialty-specific advanced practice nursing, according to the tightly regulated scope of practice defined by individual states. As stated in my editorial, psychiatric mental health (PMH) APRNs engage in the practice of advanced practice PMH nursing. Is there overlap with medicine, social work, and psychology? Of course, but we are not criticized by social workers and psychologists when we engage in various psychotherapeutic approaches; rather, we are collegial and refer to each other. Why are we criticized by physicians when we prescribe from our tightly regulated legend drugs or conduct a psychiatric intake and develop a differential diagnosis and formulation that may save a life in the absence of an available psychiatrist? I would offer that PMH-APRNs are proud of their vast history of collegial relationships with psychiatrists, and that in states where turf is not an issue, there is remarkable respect and mutual referrals based on the ultimate need of finding the most appropriate care for a patient and/or family struggling to live with a psychiatric disorder.

Currently, 26 states have legislated independent practice for APRNs. This legislation was passed after decades of compiling data on the safety and efficacy of patient care outcomes in those states, and then was submitted as testimony to the legislature. State legislature decisions often are influenced by the fact that malpractice claims are decreased in areas where APRNs are independent and increased when APRNs are associated with MDs. A 2009 study¹ found that between 1991 and 2007—the first 17 years that the National Practitioner Data Bank was in operation—payments were made on behalf of 37% of physicians but only 3.1% of physician assistants (PAs) and 1.5% of nurse practitioners. The study concluded: “There were no observations or trends to suggest that PAs and APNs increase liability. If anything, they may decrease the rate of reporting malpractice and adverse events.”¹

To respond to Dr. Kendall’s comment, “nursing was never designed to be an autonomous practice,” nursing at the entry level of registration was originally conceived by Florence Nightingale as an autonomous profession working side-by-side with physicians, each performing different yet complementary aspects of patient care, each answering to a different hierarchy. Her work in the Crimean War attests to the positive effects of nursing on saving soldiers’ lives, which was heretofore unknown due to all the measures she initiated and meticulously documented. This autonomy, however, was gradually usurped in the private sector. Comparing RNs with MDs is like comparing apples with oranges. We would need to compare all MDs with the 3.4 million registered nurses in the United States, and that is not what my editorial addressed.

For >50 years, master’s prepared advanced practice nurses in psychiatry have been independent in their ability to have private practices, initially focusing on the provision of individual, group, and family psychotherapy. Psychiatrists did not object to this because it opened services they were unable to provide. As psychopharmacologic treatments for psychiatric disorders emerged, APRNs who had the minimum of a master’s degree and substantial psycho­pharmacology education, which was mandated and regulated by states, were gradually allowed to prescribe starting in the late 1970s. Most typically, these practices were in collaboration with or under supervision of an MD, but as data and outcomes were collected, legislatures began to drop this requirement.

Regarding hours, we could compare the >2,000 classroom and clinical hours and years of clinical experience accumulated by PMH-APRNs in their undergraduate and graduate psychiatric nursing curricula with the 60-hour Psychiatric Medicine course taken in the second semester of the first year of medical school.² For many physicians, this often is the only psychiatric education they receive when going into primary care. When we consider that 70% of psychiatric care is now provided in a primary care setting, we all should be concerned and be attempting to recruit highly qualified PMH-APRNs to assist in the development and delivery of integrated primary care.

Regarding APRNs working in rural areas, Hanrahan and Hartley³ found that psychiatric APRNs were more likely than psychiatrists to live in rural areas. I contend that the issue is not the zip code of the psychiatric APRN, but rather the need to fix the problem of providers not being drawn to practice in rural and underserved populations due to salary.

Promoting autonomy for PMH-APRNs in all states is not the only way to solve the provider supply shortage, but it is a reasonable way. Unfortunately, there will be a shortage of psychiatric providers no matter what we do. Those of us who are dedicated to providing care to this vulnerable population should be finding ways to maximize our efforts and efficiencies to lessen the critical shortage. Anything less only adds to the problem and sends a negative message to the public. If we psychiatric providers cannot be supportive of each discipline practicing to the full scope and authority of their hard-earned licenses, then we are saying that we are more interested in protecting turf than providing desperately needed care.

Mary D. Moller, DNP, ARNP, PMHCNS-BC, CPRP, FAAN
Associate Professor and Coordinator PMH-DNP ProgramPacific Lutheran University School of Nursing
Director of Psychiatric Services
Northwest Integrated Health
Tacoma, Washington

References
1. Hooker RS, Nicholson JG, Le T. Does the employment of physician assistants and nurse practitioners increase liability? Journal of Medical Licensure and Discipline. 2009;95(2): 6-16.
2. Columbia University Medical Center. Medical student education in psychiatry. https://www.columbiapsychiatry.org/education-and-training/medical-student-education-psychiatry. Accessed November 16, 2017.
3. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.

In Dr. Mary Moller’s Guest Editorial “Advancing the role of advanced practice psychiatric nurses in today’s psychiatric workforce” (Current Psychiatry. April 2017, p. 15-16,18-20), she asserts that the American Psychiatric Association (APA) should take a stand against the American Medical Association (AMA) because AMA lobbyists pose a barrier to allowing advanced practice registered nurses (APRNs) to engage in autonomous practice. She argues that physician supervision is nothing more than a means of earning extra money for some physicians, calling it a “cottage industry.” Although she states that psychiatric APRNs provide skilled psychiatric care from a “nursing perspective” and argues that we “come together to respect our given scopes of practice,” the implication is clear: “to remove unnecessary barriers to practice and promote a unified and collegial workforce” is to assert that APRNs can do anything psychiatrists do. As physicians, we all know this is not the case. To support autonomous practice is to promote a reckless endeavor that endangers our patients.

Dr. Moller cited a source from the Federal Trade Commission¹ that encourages the autonomous practice of APRNs to increase competition. This again implies the false equivalency between physicians and APRNs. Competition implies that the players are providing the same service. If, as nurse practitioners argue, they practice “nursing,” then they are not practicing “medicine.” Physicians and APRNs do not have the same background. Although both are charged with the care of patients, nursing is not medicine, nor should it be. Both are important and needed, but nursing was never designed to be an autonomous practice. According to the American Association of Colleges of Nursing, “Nursing and medicine are distinct health disciplines that prepare clinicians to assume different roles and meet different practice expectations.”² In fact, the curriculum and requirements to become an APRN vary depending on the program, and some programs do not even require a BSN.³ There are online programs available for earning an APRN degree. Additionally, APRNs are only required to have 500 to 700 total hours of patient care,⁴ compared with the >10,000 hours physicians have once they have finished a 3-year residency, which when combined with their education amounts to >20,000 hours.⁵ This doesn’t account for those who have longer residencies or fellowships to further specialize in their area of training.

Dr. Moller’s main argument is that there is a dire shortage of psychiatrists and that the only way to meet this need for more providers is to make APRNs autonomous. However, no data indicate that autonomous practice of mid-level providers leads to an influx of these providers in rural areas, where the need would be greatest. Although current data on this are quite sparse, some studies indicate that the majority practice in urban areas, even in states with independent practice authority.^6,7 Dr. Moller cites a source that only reviewed home zip codes of psychiatric APRNs but did not include zip codes of employment.⁸ Only 13% of psychiatric APRNs live in rural areas across the United States. Therefore, it is a false assertion to state that these APRNs are found primarily in rural and less populated urban areas. It is also false to imply and assume that these APRNs practice in the rural areas.

In 2017, there were 43,157 registered physician applications, with 35,969 active applications for 31,757 residency positions in the United States, and at least 11,400 medical school graduates were unmatched.⁹ Imagine how much more we could serve our patients by matching these graduates, whose training far surpasses that of a mid-level provider. The Resident Physician Shortage Reduction Act of 2017 aims to address this problem by increasing Medicare-funded graduate medical education (GME) residency programs in the United States.¹⁰ We can make a difference by contacting our members of Congress to encourage them to support this bill. In addition, the AMA is advocating to save funding for GME and provides an easy-to-use Web site (https://savegme.org/take-action) to contact your legislators directly to show your support for GME.

Nurse practitioners have tremendous value when their role is a part of a team; however, they should not practice without supervision, and physicians who supervise them absolutely should be providing adequate super­vision. I applaud the APA and the AMA for standing up for the practice of medicine and for our patients. I hope that they continue to do so, and I encourage them to increase their efforts.

Laura Kendall, MD
Assistant Professor of Clinical Psychiatry
Department of Psychiatry and Behavioral Sciences
Keck School of Medicine
University of Southern California
Los Angeles, California

References
1. Koslov T; Office of Policy Planning. The doctor (or nurse practitioner) will see you now: competition and the regulation of advanced practice nurses. Federal Trade Commission. https://www.ftc.gov/news-events/blogs/competition-matters/2014/03/doctor-or-nurse-practitioner-will-see-you-now. Published March 7, 2014. Accessed July 26, 2017.
2. American Association of Colleges of Nursing. DNP talking points. http://www.aacnnursing.org/DNP/about/talking-points. Updated July, 2014. Accessed August 12, 2017.
3. Keyes L. MSN without a BSN? MastersInNursing.com. https://www.mastersinnursing.com/msn-without-a-bsn. Accessed August 12, 2017.
4. Iglehart JK. Expanding the role of advanced nurse practitioners—risks and rewards. New Engl J Med. 2013;368(20):1935-1941.
5. Primary Care Coalition. Issue brief: collaboration between physicians and nurses works. Compare the education gaps between primary care physicians and nurse practitioners. http://www.tafp.org/Media/Default/Downloads/advocacy/scope-education.pdf. Published November 1, 2010. Accessed October 11, 2017.
6. American Medical Association. Issue brief: independent nursing practice. https://www.ama-assn.org/system/files/media-browser/premium/arc/ama-issue-brief-independent-nursing-practice.pdf. Updated 2017.
7. Tabor J, Jennings N, Kohler L, et al. The supply of physician assistants, nurse practitioners, and certified nurse midwives in Arizona. University of Arizona. http://azahec.uahs.arizona.edu/sites/default/files/u9/supply_of_pa_np_cnm.pdf. Accessed October 11, 2017.
8. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.
9. 2017 NRMP Main Residency Match the largest match on record [press release]. Washington, DC: National Resident Matching Program; March 17, 2017. http://www.nrmp.org/press-release-2017-nrmp-main-residency-match-the-largest-match-on-record. Accessed October 11, 2017.
10. Resident Physician Shortage Reduction Act of 2017, HR 2267, 115th Cong, 1st session (2017).

The author responds

I would like to thank Dr. Kendall for her passionate letter about my editorial and provide the following response. I neither asserted the equivalency of doctors and nurses or that APRNs can do what MDs do. Rather, APRNs are educated to provide highly qualified, specialty-specific advanced practice nursing, according to the tightly regulated scope of practice defined by individual states. As stated in my editorial, psychiatric mental health (PMH) APRNs engage in the practice of advanced practice PMH nursing. Is there overlap with medicine, social work, and psychology? Of course, but we are not criticized by social workers and psychologists when we engage in various psychotherapeutic approaches; rather, we are collegial and refer to each other. Why are we criticized by physicians when we prescribe from our tightly regulated legend drugs or conduct a psychiatric intake and develop a differential diagnosis and formulation that may save a life in the absence of an available psychiatrist? I would offer that PMH-APRNs are proud of their vast history of collegial relationships with psychiatrists, and that in states where turf is not an issue, there is remarkable respect and mutual referrals based on the ultimate need of finding the most appropriate care for a patient and/or family struggling to live with a psychiatric disorder.

Currently, 26 states have legislated independent practice for APRNs. This legislation was passed after decades of compiling data on the safety and efficacy of patient care outcomes in those states, and then was submitted as testimony to the legislature. State legislature decisions often are influenced by the fact that malpractice claims are decreased in areas where APRNs are independent and increased when APRNs are associated with MDs. A 2009 study¹ found that between 1991 and 2007—the first 17 years that the National Practitioner Data Bank was in operation—payments were made on behalf of 37% of physicians but only 3.1% of physician assistants (PAs) and 1.5% of nurse practitioners. The study concluded: “There were no observations or trends to suggest that PAs and APNs increase liability. If anything, they may decrease the rate of reporting malpractice and adverse events.”¹

To respond to Dr. Kendall’s comment, “nursing was never designed to be an autonomous practice,” nursing at the entry level of registration was originally conceived by Florence Nightingale as an autonomous profession working side-by-side with physicians, each performing different yet complementary aspects of patient care, each answering to a different hierarchy. Her work in the Crimean War attests to the positive effects of nursing on saving soldiers’ lives, which was heretofore unknown due to all the measures she initiated and meticulously documented. This autonomy, however, was gradually usurped in the private sector. Comparing RNs with MDs is like comparing apples with oranges. We would need to compare all MDs with the 3.4 million registered nurses in the United States, and that is not what my editorial addressed.

For >50 years, master’s prepared advanced practice nurses in psychiatry have been independent in their ability to have private practices, initially focusing on the provision of individual, group, and family psychotherapy. Psychiatrists did not object to this because it opened services they were unable to provide. As psychopharmacologic treatments for psychiatric disorders emerged, APRNs who had the minimum of a master’s degree and substantial psycho­pharmacology education, which was mandated and regulated by states, were gradually allowed to prescribe starting in the late 1970s. Most typically, these practices were in collaboration with or under supervision of an MD, but as data and outcomes were collected, legislatures began to drop this requirement.

Regarding hours, we could compare the >2,000 classroom and clinical hours and years of clinical experience accumulated by PMH-APRNs in their undergraduate and graduate psychiatric nursing curricula with the 60-hour Psychiatric Medicine course taken in the second semester of the first year of medical school.² For many physicians, this often is the only psychiatric education they receive when going into primary care. When we consider that 70% of psychiatric care is now provided in a primary care setting, we all should be concerned and be attempting to recruit highly qualified PMH-APRNs to assist in the development and delivery of integrated primary care.

Regarding APRNs working in rural areas, Hanrahan and Hartley³ found that psychiatric APRNs were more likely than psychiatrists to live in rural areas. I contend that the issue is not the zip code of the psychiatric APRN, but rather the need to fix the problem of providers not being drawn to practice in rural and underserved populations due to salary.

Promoting autonomy for PMH-APRNs in all states is not the only way to solve the provider supply shortage, but it is a reasonable way. Unfortunately, there will be a shortage of psychiatric providers no matter what we do. Those of us who are dedicated to providing care to this vulnerable population should be finding ways to maximize our efforts and efficiencies to lessen the critical shortage. Anything less only adds to the problem and sends a negative message to the public. If we psychiatric providers cannot be supportive of each discipline practicing to the full scope and authority of their hard-earned licenses, then we are saying that we are more interested in protecting turf than providing desperately needed care.

Mary D. Moller, DNP, ARNP, PMHCNS-BC, CPRP, FAAN
Associate Professor and Coordinator PMH-DNP ProgramPacific Lutheran University School of Nursing
Director of Psychiatric Services
Northwest Integrated Health
Tacoma, Washington

References
1. Hooker RS, Nicholson JG, Le T. Does the employment of physician assistants and nurse practitioners increase liability? Journal of Medical Licensure and Discipline. 2009;95(2): 6-16.
2. Columbia University Medical Center. Medical student education in psychiatry. https://www.columbiapsychiatry.org/education-and-training/medical-student-education-psychiatry. Accessed November 16, 2017.
3. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.

In Dr. Mary Moller’s Guest Editorial “Advancing the role of advanced practice psychiatric nurses in today’s psychiatric workforce” (Current Psychiatry. April 2017, p. 15-16,18-20), she asserts that the American Psychiatric Association (APA) should take a stand against the American Medical Association (AMA) because AMA lobbyists pose a barrier to allowing advanced practice registered nurses (APRNs) to engage in autonomous practice. She argues that physician supervision is nothing more than a means of earning extra money for some physicians, calling it a “cottage industry.” Although she states that psychiatric APRNs provide skilled psychiatric care from a “nursing perspective” and argues that we “come together to respect our given scopes of practice,” the implication is clear: “to remove unnecessary barriers to practice and promote a unified and collegial workforce” is to assert that APRNs can do anything psychiatrists do. As physicians, we all know this is not the case. To support autonomous practice is to promote a reckless endeavor that endangers our patients.

Dr. Moller cited a source from the Federal Trade Commission¹ that encourages the autonomous practice of APRNs to increase competition. This again implies the false equivalency between physicians and APRNs. Competition implies that the players are providing the same service. If, as nurse practitioners argue, they practice “nursing,” then they are not practicing “medicine.” Physicians and APRNs do not have the same background. Although both are charged with the care of patients, nursing is not medicine, nor should it be. Both are important and needed, but nursing was never designed to be an autonomous practice. According to the American Association of Colleges of Nursing, “Nursing and medicine are distinct health disciplines that prepare clinicians to assume different roles and meet different practice expectations.”² In fact, the curriculum and requirements to become an APRN vary depending on the program, and some programs do not even require a BSN.³ There are online programs available for earning an APRN degree. Additionally, APRNs are only required to have 500 to 700 total hours of patient care,⁴ compared with the >10,000 hours physicians have once they have finished a 3-year residency, which when combined with their education amounts to >20,000 hours.⁵ This doesn’t account for those who have longer residencies or fellowships to further specialize in their area of training.

Dr. Moller’s main argument is that there is a dire shortage of psychiatrists and that the only way to meet this need for more providers is to make APRNs autonomous. However, no data indicate that autonomous practice of mid-level providers leads to an influx of these providers in rural areas, where the need would be greatest. Although current data on this are quite sparse, some studies indicate that the majority practice in urban areas, even in states with independent practice authority.^6,7 Dr. Moller cites a source that only reviewed home zip codes of psychiatric APRNs but did not include zip codes of employment.⁸ Only 13% of psychiatric APRNs live in rural areas across the United States. Therefore, it is a false assertion to state that these APRNs are found primarily in rural and less populated urban areas. It is also false to imply and assume that these APRNs practice in the rural areas.

In 2017, there were 43,157 registered physician applications, with 35,969 active applications for 31,757 residency positions in the United States, and at least 11,400 medical school graduates were unmatched.⁹ Imagine how much more we could serve our patients by matching these graduates, whose training far surpasses that of a mid-level provider. The Resident Physician Shortage Reduction Act of 2017 aims to address this problem by increasing Medicare-funded graduate medical education (GME) residency programs in the United States.¹⁰ We can make a difference by contacting our members of Congress to encourage them to support this bill. In addition, the AMA is advocating to save funding for GME and provides an easy-to-use Web site (https://savegme.org/take-action) to contact your legislators directly to show your support for GME.

Nurse practitioners have tremendous value when their role is a part of a team; however, they should not practice without supervision, and physicians who supervise them absolutely should be providing adequate super­vision. I applaud the APA and the AMA for standing up for the practice of medicine and for our patients. I hope that they continue to do so, and I encourage them to increase their efforts.

Laura Kendall, MD
Assistant Professor of Clinical Psychiatry
Department of Psychiatry and Behavioral Sciences
Keck School of Medicine
University of Southern California
Los Angeles, California

References
1. Koslov T; Office of Policy Planning. The doctor (or nurse practitioner) will see you now: competition and the regulation of advanced practice nurses. Federal Trade Commission. https://www.ftc.gov/news-events/blogs/competition-matters/2014/03/doctor-or-nurse-practitioner-will-see-you-now. Published March 7, 2014. Accessed July 26, 2017.
2. American Association of Colleges of Nursing. DNP talking points. http://www.aacnnursing.org/DNP/about/talking-points. Updated July, 2014. Accessed August 12, 2017.
3. Keyes L. MSN without a BSN? MastersInNursing.com. https://www.mastersinnursing.com/msn-without-a-bsn. Accessed August 12, 2017.
4. Iglehart JK. Expanding the role of advanced nurse practitioners—risks and rewards. New Engl J Med. 2013;368(20):1935-1941.
5. Primary Care Coalition. Issue brief: collaboration between physicians and nurses works. Compare the education gaps between primary care physicians and nurse practitioners. http://www.tafp.org/Media/Default/Downloads/advocacy/scope-education.pdf. Published November 1, 2010. Accessed October 11, 2017.
6. American Medical Association. Issue brief: independent nursing practice. https://www.ama-assn.org/system/files/media-browser/premium/arc/ama-issue-brief-independent-nursing-practice.pdf. Updated 2017.
7. Tabor J, Jennings N, Kohler L, et al. The supply of physician assistants, nurse practitioners, and certified nurse midwives in Arizona. University of Arizona. http://azahec.uahs.arizona.edu/sites/default/files/u9/supply_of_pa_np_cnm.pdf. Accessed October 11, 2017.
8. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.
9. 2017 NRMP Main Residency Match the largest match on record [press release]. Washington, DC: National Resident Matching Program; March 17, 2017. http://www.nrmp.org/press-release-2017-nrmp-main-residency-match-the-largest-match-on-record. Accessed October 11, 2017.
10. Resident Physician Shortage Reduction Act of 2017, HR 2267, 115th Cong, 1st session (2017).

The author responds

I would like to thank Dr. Kendall for her passionate letter about my editorial and provide the following response. I neither asserted the equivalency of doctors and nurses or that APRNs can do what MDs do. Rather, APRNs are educated to provide highly qualified, specialty-specific advanced practice nursing, according to the tightly regulated scope of practice defined by individual states. As stated in my editorial, psychiatric mental health (PMH) APRNs engage in the practice of advanced practice PMH nursing. Is there overlap with medicine, social work, and psychology? Of course, but we are not criticized by social workers and psychologists when we engage in various psychotherapeutic approaches; rather, we are collegial and refer to each other. Why are we criticized by physicians when we prescribe from our tightly regulated legend drugs or conduct a psychiatric intake and develop a differential diagnosis and formulation that may save a life in the absence of an available psychiatrist? I would offer that PMH-APRNs are proud of their vast history of collegial relationships with psychiatrists, and that in states where turf is not an issue, there is remarkable respect and mutual referrals based on the ultimate need of finding the most appropriate care for a patient and/or family struggling to live with a psychiatric disorder.

Currently, 26 states have legislated independent practice for APRNs. This legislation was passed after decades of compiling data on the safety and efficacy of patient care outcomes in those states, and then was submitted as testimony to the legislature. State legislature decisions often are influenced by the fact that malpractice claims are decreased in areas where APRNs are independent and increased when APRNs are associated with MDs. A 2009 study¹ found that between 1991 and 2007—the first 17 years that the National Practitioner Data Bank was in operation—payments were made on behalf of 37% of physicians but only 3.1% of physician assistants (PAs) and 1.5% of nurse practitioners. The study concluded: “There were no observations or trends to suggest that PAs and APNs increase liability. If anything, they may decrease the rate of reporting malpractice and adverse events.”¹

To respond to Dr. Kendall’s comment, “nursing was never designed to be an autonomous practice,” nursing at the entry level of registration was originally conceived by Florence Nightingale as an autonomous profession working side-by-side with physicians, each performing different yet complementary aspects of patient care, each answering to a different hierarchy. Her work in the Crimean War attests to the positive effects of nursing on saving soldiers’ lives, which was heretofore unknown due to all the measures she initiated and meticulously documented. This autonomy, however, was gradually usurped in the private sector. Comparing RNs with MDs is like comparing apples with oranges. We would need to compare all MDs with the 3.4 million registered nurses in the United States, and that is not what my editorial addressed.

For >50 years, master’s prepared advanced practice nurses in psychiatry have been independent in their ability to have private practices, initially focusing on the provision of individual, group, and family psychotherapy. Psychiatrists did not object to this because it opened services they were unable to provide. As psychopharmacologic treatments for psychiatric disorders emerged, APRNs who had the minimum of a master’s degree and substantial psycho­pharmacology education, which was mandated and regulated by states, were gradually allowed to prescribe starting in the late 1970s. Most typically, these practices were in collaboration with or under supervision of an MD, but as data and outcomes were collected, legislatures began to drop this requirement.

Regarding hours, we could compare the >2,000 classroom and clinical hours and years of clinical experience accumulated by PMH-APRNs in their undergraduate and graduate psychiatric nursing curricula with the 60-hour Psychiatric Medicine course taken in the second semester of the first year of medical school.² For many physicians, this often is the only psychiatric education they receive when going into primary care. When we consider that 70% of psychiatric care is now provided in a primary care setting, we all should be concerned and be attempting to recruit highly qualified PMH-APRNs to assist in the development and delivery of integrated primary care.

Regarding APRNs working in rural areas, Hanrahan and Hartley³ found that psychiatric APRNs were more likely than psychiatrists to live in rural areas. I contend that the issue is not the zip code of the psychiatric APRN, but rather the need to fix the problem of providers not being drawn to practice in rural and underserved populations due to salary.

Promoting autonomy for PMH-APRNs in all states is not the only way to solve the provider supply shortage, but it is a reasonable way. Unfortunately, there will be a shortage of psychiatric providers no matter what we do. Those of us who are dedicated to providing care to this vulnerable population should be finding ways to maximize our efforts and efficiencies to lessen the critical shortage. Anything less only adds to the problem and sends a negative message to the public. If we psychiatric providers cannot be supportive of each discipline practicing to the full scope and authority of their hard-earned licenses, then we are saying that we are more interested in protecting turf than providing desperately needed care.

Mary D. Moller, DNP, ARNP, PMHCNS-BC, CPRP, FAAN
Associate Professor and Coordinator PMH-DNP ProgramPacific Lutheran University School of Nursing
Director of Psychiatric Services
Northwest Integrated Health
Tacoma, Washington

References
1. Hooker RS, Nicholson JG, Le T. Does the employment of physician assistants and nurse practitioners increase liability? Journal of Medical Licensure and Discipline. 2009;95(2): 6-16.
2. Columbia University Medical Center. Medical student education in psychiatry. https://www.columbiapsychiatry.org/education-and-training/medical-student-education-psychiatry. Accessed November 16, 2017.
3. Hanrahan NP, Hartley D. Employment of advanced-practice psychiatric nurses to stem rural mental health workforce shortages. Psychiatr Serv. 2008;59(1):109-111.

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

© Todd Buchanan 2017

ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.

The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.

The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.

Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).

Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.

“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.

Study design

Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.

Maintenance therapy was initiated within 60 to 180 days after transplant. It  consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.

After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.

Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.

“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”

Patient characteristics

The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).

Forty-two patients (66%) were male, and 22 were female.

Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.

At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).

Safety

Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.

Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.

Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.

“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”

Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.

Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).

Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).

Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.

Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).

Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).

Dose reductions

Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.

Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).

Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).

Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.

All patients started lenalidomide at 10 mg for 28 days.

Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.

Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).

Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).

“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.

Efficacy

Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.

Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.

The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.

At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.

The median PFS for patients with high-risk disease is 21.85 months.

Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.

Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.

The study was supported by Takeda Oncology.

* Data in the presentation differ slightly from the abstract.

© Todd Buchanan 2017

ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.

The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.

The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.

Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).

Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.

“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.

Study design

Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.

Maintenance therapy was initiated within 60 to 180 days after transplant. It  consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.

After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.

Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.

“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”

Patient characteristics

The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).

Forty-two patients (66%) were male, and 22 were female.

Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.

At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).

Safety

Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.

Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.

Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.

“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”

Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.

Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).

Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).

Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.

Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).

Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).

Dose reductions

Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.

Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).

Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).

Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.

All patients started lenalidomide at 10 mg for 28 days.

Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.

Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).

Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).

“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.

Efficacy

Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.

Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.

The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.

At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.

The median PFS for patients with high-risk disease is 21.85 months.

Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.

Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.

The study was supported by Takeda Oncology.

* Data in the presentation differ slightly from the abstract.

© Todd Buchanan 2017

ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.

The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.

The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.

Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).

Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.

“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.

Study design

Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.

Maintenance therapy was initiated within 60 to 180 days after transplant. It  consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.

After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.

Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.

“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”

Patient characteristics

The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).

Forty-two patients (66%) were male, and 22 were female.

Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.

At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).

Safety

Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.

Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.

Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.

“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”

Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.

Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).

Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).

Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.

Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).

Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).

Dose reductions

Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.

Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).

Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).

Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.

All patients started lenalidomide at 10 mg for 28 days.

Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.

Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).

Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).

“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.

Efficacy

Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.

Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.

The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.

At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.

The median PFS for patients with high-risk disease is 21.85 months.

Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.

Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.

The study was supported by Takeda Oncology.

* Data in the presentation differ slightly from the abstract.

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; drbrink@umn.edu.

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; drbrink@umn.edu.

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; drbrink@umn.edu.