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CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Depression has been studied extensively in relation to cardiovascular disease.^1–3 In addition to depression, anger⁴ and anxiety⁵ also may promote coronary artery disease (CAD), suggesting that emotional distress in general may be related to increased cardiovascular risk. Evidence indicates that the general distress shared across depression, anger, and anxiety predicts CAD, even after controlling for each of these specific negative emotions.⁶

THE CONCEPT OF TYPE D PERSONALITY

Lately, there is a renewed interest in broad individual differences in general distress and heart disease.⁷ Since psychologic factors often cluster together in individual patients, biobehavioral research may benefit from the identification of discrete personality subtypes.⁸ This focus on the identification of psychologically vulnerable patients who are at increased risk for adverse outcomes has led to the introduction of the distressed⁹ or type D¹⁰ personality profile in cardiovascular research. This personality construct is defined as follows:

“The type D (distressed) personality profile refers to a general propensity to psychological distress that is characterized by the combination of negative affectivity and social inhibition.”¹⁰

Negative affectivity, or the tendency to experience negative emotions across time and situations, is a major determinant of emotional distress in cardiac patients.^9,10 Patients who score high on this trait frequently report feelings of dysphoria, worry, and tension. Social inhibition, or the tendency to inhibit the expression of emotions or behavior, is a major determinant of social distress.^9,10 Patients who score high on this trait tend to avoid negative reactions from others.

Both traits define psychologically vulnerable patients and can be assessed with the type D scale (DS14).¹⁰ This brief measure consists of a seven-item negative affectivity subscale (eg, I often feel unhappy) and a seven-item inhibition subscale (eg, I am inhibited in social interactions), and has a clear two-factor structure and good reliability (Cronbach’s α = .88 and .86). Patients are classified as type D if they score 10 or higher on both DS14 subscales.¹⁰ The prevalence of type D personality ranges between 20% and 40% across different types of cardiovascular conditions.

The type D construct was designed for the early identification of chronically distressed patients. This article reviews (1) the risk of adverse events associated with type D, (2) the extent to which type D is distinct from depression, (3) the biologic pathways of type D, and (4) the implications of the type D personality profile.

RISK ASSOCIATED WITH TYPE D

The relationship between type D personality and adverse events has also been investigated in other cardiovascular conditions. Type D has been associated with poor prognosis in patients with peripheral arterial disease,¹⁷ but evidence for the prognostic role of type D in patients with chronic heart failure is mixed. In a study of patients with heart failure following myocardial infarction, type D predicted cardiac death independent of disease severity¹⁸; in a study of heart failure patients who underwent cardiac transplantation, type D was associated with early allograft rejection and increased mortality.¹⁹ However, type D was not associated with cardiac death in a recent, larger heart failure study.²⁰ The link between psychologic factors and heart failure is complex³ and may be less obvious than the type D-CAD link.²⁰ Type D has also been associated with the occurrence of life-threatening arrhythmias following implantable cardioverter defibrillator (ICD) treatment,²¹ and it has been shown to predict an increased risk for mortality in ICD patients, independent from shocks and disease severity.²²

The wide range in odds ratios and confidence intervals indicates disparity in data across these type D studies (Table 1). We recently performed a metaanalysis of prospective studies between 1996 and 2009 to provide a more reliable estimate of the risk associated with type D. In this analysis, type D was associated with a threefold increased risk of adverse events²³; the confidence interval of this pooled odds ratio ranged from 2.7 to 5.1. In addition, type D personality was associated with a threefold increased risk (range, 2.6 to 4.3) of emotional distress over time.²³ From the recent studies that were not included in this meta-analysis, one reported negative findings²⁰ and three others positive findings^16,21,22 on the risk associated with type D.

COMPARING DEPRESSION AND TYPE D

Clinical evidence shows that, after adjustment for depression, type D remained a predictor of adverse cardiac events in CAD.^16,24,25 Following ICD implantation, anxious type D patients were at risk of ventricular arrhythmias, whereas depression did not predict arrhythmias.²¹ Type D also exerts an adverse effect on patients’ health status following coronary bypass surgery,²⁶ heart failure,²⁷ or myocardial infarction,²⁸ adjusting for depressive symptoms. Type D is related to biomarkers of increased stress levels independent of depression^29–31 and, unlike depression, type D is not confounded by the severity of cardiac disorder.³²

Following myocardial infarction, only one of four distressed patients met criteria for both type D and depression; most had one form of distress but not the other.³² Research in healthy³³ and in cardiac³⁴ populations confirmed that items from depression and type D scales reflect different distress factors. After adjustment for depression at baseline, type D also predicted the incidence,³⁵ persistence,³⁶ and severity^37,38 of depression and anxiety. However, these findings do not imply that depression and type D are antonymous perspectives or that one perspective is better than the other in predicting outcomes; rather, we would like to argue that both constructs represent complementary perspectives that have added value.²³

BIOLOGIC PATHWAYS OF TYPE D

Other studies found that type D was associated with inflammatory dysregulation. In healthy adults, type D has been related to higher concentrations of C-reactive protein.⁴¹ In heart failure patients, type D is associated with increased plasma levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α and its soluble receptors 1 and 2.^46,47 Increased TNF-α levels may cause suppression of bone-marrow–derived endothelial progenitor cells (EPCs) that play an important role in maintaining vascular integrity. The negative affectivity component of type D has been shown to predict decreased circulating EPC counts in healthy individuals⁴⁸; another study found that these EPC numbers were reduced by more than 50% in heart failure patients with a type D personality.⁴⁹ Type D personality is also associated with an increased oxidative stress burden in patients with chronic heart failure.²⁹ Studies on genetic linkage⁵⁰ and heritability⁵¹ further support biologic underpinnings of the type D construct.

Regarding pathways that may explain the effect of type D, some issues are of special interest. First, genetic factors contribute to stability in type D personality, but environmental factors may induce changes in type D characteristics over time.⁵¹ Hence, given this role of environmental influences over time, behavioral intervention would be feasible and useful in type D patients. Second, type D can promote heart disease indirectly through behavioral pathways. Type D has been associated with a sedentary lifestyle,^41,52 an unhealthy diet,⁵³ and a passive coping style.^54,55 Poor adherence to medical treatment^56,57 and reluctance to consult clinical staff⁵⁸ may jeopardize the working relationship with type D patients in clinical care. Intervention may focus on the management of these behavioral risk factors in type D patients. Third, many of these biologic^{40–43,48,50,51} and behavioral^41,52–54 pathways have also been documented in healthy type D individuals, which suggests that these associations cannot be explained away by the confounding effect of underlying cardiovascular disease.

CLINICAL IMPLICATIONS OF TYPE D

The findings from type D research have a number of clinical implications. Type D is associated with an increased risk of adverse events,²³ chronic distress,^35–38 and suicidal ideation.⁵⁹ Type D may also have an adverse effect on the outcome of invasive treatment.^{14,19,21,22,24,26,60}

Type D was associated with mortality and morbidity at 9 months¹⁴ and 2 years²⁴ following coronary artery stenting, and with impaired health status 1 year following bypass surgery.²⁶ Type D also predicted mortality and allograft rejection following heart transplantation,¹⁹ and an increased risk of ventricular arrhythmia²¹ and mortality²² in ICD patients. Researchers from the Cleveland Clinic have shown that type D is a risk factor for anxiety in ICD patients.⁶⁰

Regarding the DSM-IV classification by the American Psychiatric Association,⁶¹ type D qualifies for the diagnosis “psychological factors affecting medical condition” (Section 316). In keeping with this classification, the diagnostic category type D affects (1) the course of cardiovascular conditions,²³ (2) the treatment of these conditions,^56,57 and (3) the working relationship with medical staff.⁵⁸ At present, no clinical trial has examined whether intervention for distress among type D patients alters their risk for adverse events. Nevertheless, some have argued that it is plausible for type D patients to learn new strategies to reduce their level of general distress.⁶² Previous research with patients experiencing symptoms like those of type D patients suggests that psychotherapy, social skills training, stress management, and relaxation training may reduce stress in these patients and improve their ability to express their emotions to others.⁶² Others have suggested that stress management training, including communication skills and problem-solving, may further improve the risk profile and health in cardiac patients.⁶³

It is possible that type D patients may benefit from close monitoring of their clinical condition and from aggressive management of their risk factor profile to prevent adverse clinical events. Cardiac rehabilitation is an effective approach to treating risk factors and enhancing well-being in CAD.^63,64 A few studies have examined the effect of cardiac rehabilitation in type D patients. One study found a significant decrease in the social inhibition component of type D following cardiac rehabilitation, but there was no change in the prevalence of type D at 1-year follow-up.⁶⁵ Although the type D profile tends to remain stable during rehabilitation,^65,66 evidence shows that type D patients who participate in cardiac rehabilitation improve in physical and mental health status.⁶⁶ Cardiac rehabilitation may also ward off further deterioration in negative affect,⁶⁷ which, in turn, has been associated with better survival in patients who participated in rehabilitation.⁶⁸ Future studies need to examine the effect of cardiac rehabilitation and other personalized approaches to treatment in type D patients.

CONCLUSIONS

General distress shared across negative emotions^6,23 may partly account for the role of depression, anxiety, and anger in cardiovascular disorders.^1–5 Some cardiac patients are more likely to experience distress than others. Type D may identify these psychologically vulnerable patients who tend to experience general distress.²³ This propensity to general distress differs from depression, predicts adverse outcomes, is linked to plausible biologic pathways, and highlights the chronic nature of psychologic distress in some cardiac patients.

After adjustment for depression, type D remains significantly associated with an increased risk of adverse events in patients with CAD.^16,24,25 However, this association is less obvious in patients with heart failure, and type D did not predict survival in one heart failure study.²⁰ Although initial findings suggest a number of plausible biologic and behavioral pathways, more research is needed to explain the adverse effect of type D on cardiovascular outcomes. Future research also needs to investigate whether type D patients may benefit from close monitoring of their risk factors and a more personalized approach to behavioral and cardiac treatment.

Overall, the current understanding of type D indicates that general distress should not be ignored in the link between mind and heart, and that cardiovascular patients who have a type D personality profile are particularly vulnerable to the adverse clinical effects of general distress. The DS14¹⁰ is a brief, well-validated measure of type D that could be incorporated into clinical research and practice to identify patients who are at risk of chronic distress and poor prognosis.