From the Editor

Case: Patient seeks clarification and next steps on her breast density classification
Your patient, a 51-year-old postmenopausal woman (G0P0) in good health, had an annual screening mammogram that showed no evidence of malignancy. She is white and has a mother with a history of breast cancer. She has never had a breast biopsy. Following the mammogram, she received a letter from the imaging center, stating:

She calls your office and asks, “What should I do next?”

Breasts are composed of fibrous, glandular, and adipose tissue. If the breasts contain a lot of fibrous and glandular tissue, and little adipose tissue, they are considered to be “dense.” Using mammography, the current standard is to report the density of breast tissue using 4 categories:

Dense breast tissue is defined to include the 2 categories heterogeneously dense and extremely dense.

Observational studies have reported that dense breast tissue is associated with an increased risk of breast cancer, and dense breast tissue makes it more difficult to detect breast cancer on mammography. According to data from the Breast Cancer Surveillance Consortium, among women aged 50 or older, the relative risk of breast cancer stratified by the 4 categories of breast density is 0.59, 1.00, 1.46, and 1.77, for almost entirely fatty, scattered fibroglandular densities, heterogeneously dense, and extremely dense, respectively.¹ In one study, the sensitivity of mammography to detect breast cancer was 82% to 88% for women with nondense breasts and 62% to 69% in women with dense breasts.² These data have catalyzed investigators to explore the use of supplemental imaging to enhance cancer detection in women with dense breasts.

The link between breast density and breast cancer risk and reduced sensitivity of mammography also has catalyzed activists and legislators to champion breast density notification laws, which have passed in more than 20 states. These laws require facilities that perform mammography to notify women with dense breasts that this finding is associated with an increased risk of breast cancer and that dense breasts reduce the ability of mammography to detect cancer. In some states, the law mandates that women with dense breasts be offered supplemental ultrasound imaging and that insurers must cover the cost of the ultrasound studies. Many of the laws recommend that the patient discuss the situation with the clinician who ordered the mammogram.

When I first saw the recommendation for patients to contact me about how to manage dense breasts, my initial response was, “Who? Me?” I felt ill equipped to provide any useful advice and suspected that many of my patients knew more than I about this issue.

Based on a review of the evidence, my current clinical recommendation is outlined in the 2 options below, including a low-resource utilization option and a high-resource utilization option. For patients, physicians, and health systems that are concerned that excessive breast cancer screening tests might cause more harm than benefit, the identification of dense breasts on mammogram is unlikely to be a trigger to perform any additional testing. In this situation, the pragmatic low-resource option is most relevant.

Alternatively, for patients and physicians who strongly believe in the value of screening mammography (see “Utilize tomosynthesis digital mammography technology for your patients” below), a reasonable strategy is to recommend that women with dense breasts and an increased risk for breast cancer be offered supplemental imaging.

In this editorial I elaborate these 2 approaches to breast cancer screening in women with dense breasts.
 

A pragmatic, low-resource utilization screening approach for women with dense breasts
There are no published randomized clinical trials that provide high-quality evidence on what to do if dense breasts are identified on mammography.³ Authors of observational studies have evaluated the potential role of supplemental imaging, including ultrasound and magnetic resonance imaging (MRI), in the management of dense breast tissue (see “Supplemental breast cancer screening modalities” below). Supplemental imaging involves complex trade-offs, balancing the potential benefit of identifying occult early breast cancer lesions not identified by mammography with the risk of subjecting many women without cancer to additional testing and unnecessary biopsies.

A pragmatic, low-resource utilization plan for women with dense breasts involves emphasizing that mammography is the best available screening tool and that annual or biennial mammography is the foundation of all current approaches to breast cancer screening. Supplemental imaging is unnecessary with this approach because there is no evidence that it reduces breast cancer mortality. There is, however, substantial evidence that using supplemental imaging for all women with dense breasts will result in little benefit and great costs, including many unnecessary biopsies.^1,4 Women with dense breasts also could consider annual clinical breast examination.

 

A high-resource utilization screening approach
There are no randomized trials to help guide recommendations about how to respond to a finding of dense breasts on mammography. In addition to breast density, many factors influence breast cancer risk, including a patient’s:

Women with both dense breasts and an increased risk of breast cancer may reap the greatest benefit from supplemental imaging, such as ultrasonography. Therefore, a two-step approach can help.

Step 1: Assess breast cancer risk. This can be accomplished using one of many calculators. Three that are commonly used are the:

The BCSC calculator uses age, race/ethnicity, first-degree relatives with breast cancer, a history of a breast biopsy, and breast density to calculate a 5-year risk of developing breast cancer.

The BCRAT tool uses current age, race/ethnicity, age at menarche, age at first live-birth of a child, number of first-degree relatives with breast cancer, a history of breast biopsies, and the identification of atypical hyperplasia to calculate a 5-year risk of breast cancer.

The IBIS model uses many more variables, including a detailed family history to calculate a 10-year and lifetime risk of breast cancer. If a patient has ductal carcinoma in situ, lobular carcinoma in situ, chest irradiation before age 30 years, or known BRCA1 or BRCA2 mutations, she is instructed not to use the risk calculators because they are at very high risk for breast cancer, and they need an individualized intensive plan for monitoring and prevention (see MRI section in “Supplemental breast cancer screening modalities” above).

Step 2: Use breast density and breast cancer risk to develop a screening plan. The NIH Breast Cancer Surveillance Consortium has published data estimating the risk that a woman with a mammogram negative for cancer will develop breast cancer within the next 12 months (based on her age, breast density, and breast cancer risk—calculated with the BCSC tool).⁸

It reported an increased risk of breast cancer diagnosed within 12 months following a mammogram that was negative for cancer in women with extremely dense breasts and a BCSC 5-year risk of breast cancer of 1.67% or greater and in women with heterogeneously dense breasts and a BCSC 5-year risk of breast cancer of 2.5% or greater.⁸

Using these cutoffs it is estimated that 24% of all women with heterogeneously or extremely dense breasts would be offered supplemental screening with a modality such as ultrasound, and 76% would be guided not to have supplemental screening because their risk of developing breast cancer in the 12 months following their negative mammogram is low.

If this guidance is followed, it would require 694 supplemental ultrasound studies and many biopsies to detect 1 additional breast cancer, significantly increasing overall health care costs.⁸ In many states insurers do not cover supplemental ultrasound imaging of the breasts. In most states insurers require preauthorization for supplemental MRI of the breasts. You need to know the insurance practices in the state to help guide decision making about supplemental imaging. The approach described above is consistent with the American College of Obstetricians and Gynecologists recommendation that women with dense breasts, who are asymptomaticand have no additional risk factors for breast cancer, do not need to be offered supplemental imaging.⁹

Case: Next steps
The BCSC calculator reveals that the 51-year-old woman with a family history of breast cancer and a mammogram showing extremely dense breasts has a 5-year risk of breast cancer of 2.68%. Given that this risk is elevated, this patient could be offered supplemental ultrasound screening and annual breast clinical examination. In addition, she could be further counseled about breast cancer chemoprevention options.¹⁰

Women with a strong family history of breast and/or ovarian cancer also could be referred for genetic counseling and BRCA testing.¹¹ The risk of having a BRCA mutation can be calculated using the BRCAPRO tool.¹²

Most women with dense breast tissue on mammography will never develop breast cancer. Yet the presence of dense breast tissue both increases the risk of breast cancer and decreases the sensitivity of mammography to detect cancer. There are no high-quality data from randomized trials to help guide our recommendations concerning the management of dense breasts identified on mammography. Yet many states have laws that suggest patients ask you to provide advice about breast density.

Patients, clinicians, and health systems vary in their confidence in the clinical value of breast cancer screening programs. Consequently, there is no “right answer” to this vexing problem. The standard of care is to support a range of options tailored to the specific clinical characteristics and needs of each patient. 
 

Case: Patient seeks clarification and next steps on her breast density classification
Your patient, a 51-year-old postmenopausal woman (G0P0) in good health, had an annual screening mammogram that showed no evidence of malignancy. She is white and has a mother with a history of breast cancer. She has never had a breast biopsy. Following the mammogram, she received a letter from the imaging center, stating:

She calls your office and asks, “What should I do next?”

Breasts are composed of fibrous, glandular, and adipose tissue. If the breasts contain a lot of fibrous and glandular tissue, and little adipose tissue, they are considered to be “dense.” Using mammography, the current standard is to report the density of breast tissue using 4 categories:

Dense breast tissue is defined to include the 2 categories heterogeneously dense and extremely dense.

Observational studies have reported that dense breast tissue is associated with an increased risk of breast cancer, and dense breast tissue makes it more difficult to detect breast cancer on mammography. According to data from the Breast Cancer Surveillance Consortium, among women aged 50 or older, the relative risk of breast cancer stratified by the 4 categories of breast density is 0.59, 1.00, 1.46, and 1.77, for almost entirely fatty, scattered fibroglandular densities, heterogeneously dense, and extremely dense, respectively.¹ In one study, the sensitivity of mammography to detect breast cancer was 82% to 88% for women with nondense breasts and 62% to 69% in women with dense breasts.² These data have catalyzed investigators to explore the use of supplemental imaging to enhance cancer detection in women with dense breasts.

The link between breast density and breast cancer risk and reduced sensitivity of mammography also has catalyzed activists and legislators to champion breast density notification laws, which have passed in more than 20 states. These laws require facilities that perform mammography to notify women with dense breasts that this finding is associated with an increased risk of breast cancer and that dense breasts reduce the ability of mammography to detect cancer. In some states, the law mandates that women with dense breasts be offered supplemental ultrasound imaging and that insurers must cover the cost of the ultrasound studies. Many of the laws recommend that the patient discuss the situation with the clinician who ordered the mammogram.

When I first saw the recommendation for patients to contact me about how to manage dense breasts, my initial response was, “Who? Me?” I felt ill equipped to provide any useful advice and suspected that many of my patients knew more than I about this issue.

Based on a review of the evidence, my current clinical recommendation is outlined in the 2 options below, including a low-resource utilization option and a high-resource utilization option. For patients, physicians, and health systems that are concerned that excessive breast cancer screening tests might cause more harm than benefit, the identification of dense breasts on mammogram is unlikely to be a trigger to perform any additional testing. In this situation, the pragmatic low-resource option is most relevant.

Alternatively, for patients and physicians who strongly believe in the value of screening mammography (see “Utilize tomosynthesis digital mammography technology for your patients” below), a reasonable strategy is to recommend that women with dense breasts and an increased risk for breast cancer be offered supplemental imaging.

In this editorial I elaborate these 2 approaches to breast cancer screening in women with dense breasts.
 

A pragmatic, low-resource utilization screening approach for women with dense breasts
There are no published randomized clinical trials that provide high-quality evidence on what to do if dense breasts are identified on mammography.³ Authors of observational studies have evaluated the potential role of supplemental imaging, including ultrasound and magnetic resonance imaging (MRI), in the management of dense breast tissue (see “Supplemental breast cancer screening modalities” below). Supplemental imaging involves complex trade-offs, balancing the potential benefit of identifying occult early breast cancer lesions not identified by mammography with the risk of subjecting many women without cancer to additional testing and unnecessary biopsies.

A pragmatic, low-resource utilization plan for women with dense breasts involves emphasizing that mammography is the best available screening tool and that annual or biennial mammography is the foundation of all current approaches to breast cancer screening. Supplemental imaging is unnecessary with this approach because there is no evidence that it reduces breast cancer mortality. There is, however, substantial evidence that using supplemental imaging for all women with dense breasts will result in little benefit and great costs, including many unnecessary biopsies.^1,4 Women with dense breasts also could consider annual clinical breast examination.

 

A high-resource utilization screening approach
There are no randomized trials to help guide recommendations about how to respond to a finding of dense breasts on mammography. In addition to breast density, many factors influence breast cancer risk, including a patient’s:

Women with both dense breasts and an increased risk of breast cancer may reap the greatest benefit from supplemental imaging, such as ultrasonography. Therefore, a two-step approach can help.

Step 1: Assess breast cancer risk. This can be accomplished using one of many calculators. Three that are commonly used are the:

The BCSC calculator uses age, race/ethnicity, first-degree relatives with breast cancer, a history of a breast biopsy, and breast density to calculate a 5-year risk of developing breast cancer.

The BCRAT tool uses current age, race/ethnicity, age at menarche, age at first live-birth of a child, number of first-degree relatives with breast cancer, a history of breast biopsies, and the identification of atypical hyperplasia to calculate a 5-year risk of breast cancer.

The IBIS model uses many more variables, including a detailed family history to calculate a 10-year and lifetime risk of breast cancer. If a patient has ductal carcinoma in situ, lobular carcinoma in situ, chest irradiation before age 30 years, or known BRCA1 or BRCA2 mutations, she is instructed not to use the risk calculators because they are at very high risk for breast cancer, and they need an individualized intensive plan for monitoring and prevention (see MRI section in “Supplemental breast cancer screening modalities” above).

Step 2: Use breast density and breast cancer risk to develop a screening plan. The NIH Breast Cancer Surveillance Consortium has published data estimating the risk that a woman with a mammogram negative for cancer will develop breast cancer within the next 12 months (based on her age, breast density, and breast cancer risk—calculated with the BCSC tool).⁸

It reported an increased risk of breast cancer diagnosed within 12 months following a mammogram that was negative for cancer in women with extremely dense breasts and a BCSC 5-year risk of breast cancer of 1.67% or greater and in women with heterogeneously dense breasts and a BCSC 5-year risk of breast cancer of 2.5% or greater.⁸

Using these cutoffs it is estimated that 24% of all women with heterogeneously or extremely dense breasts would be offered supplemental screening with a modality such as ultrasound, and 76% would be guided not to have supplemental screening because their risk of developing breast cancer in the 12 months following their negative mammogram is low.

If this guidance is followed, it would require 694 supplemental ultrasound studies and many biopsies to detect 1 additional breast cancer, significantly increasing overall health care costs.⁸ In many states insurers do not cover supplemental ultrasound imaging of the breasts. In most states insurers require preauthorization for supplemental MRI of the breasts. You need to know the insurance practices in the state to help guide decision making about supplemental imaging. The approach described above is consistent with the American College of Obstetricians and Gynecologists recommendation that women with dense breasts, who are asymptomaticand have no additional risk factors for breast cancer, do not need to be offered supplemental imaging.⁹

Case: Next steps
The BCSC calculator reveals that the 51-year-old woman with a family history of breast cancer and a mammogram showing extremely dense breasts has a 5-year risk of breast cancer of 2.68%. Given that this risk is elevated, this patient could be offered supplemental ultrasound screening and annual breast clinical examination. In addition, she could be further counseled about breast cancer chemoprevention options.¹⁰

Women with a strong family history of breast and/or ovarian cancer also could be referred for genetic counseling and BRCA testing.¹¹ The risk of having a BRCA mutation can be calculated using the BRCAPRO tool.¹²

Most women with dense breast tissue on mammography will never develop breast cancer. Yet the presence of dense breast tissue both increases the risk of breast cancer and decreases the sensitivity of mammography to detect cancer. There are no high-quality data from randomized trials to help guide our recommendations concerning the management of dense breasts identified on mammography. Yet many states have laws that suggest patients ask you to provide advice about breast density.

Patients, clinicians, and health systems vary in their confidence in the clinical value of breast cancer screening programs. Consequently, there is no “right answer” to this vexing problem. The standard of care is to support a range of options tailored to the specific clinical characteristics and needs of each patient. 
 

Case: Patient seeks clarification and next steps on her breast density classification
Your patient, a 51-year-old postmenopausal woman (G0P0) in good health, had an annual screening mammogram that showed no evidence of malignancy. She is white and has a mother with a history of breast cancer. She has never had a breast biopsy. Following the mammogram, she received a letter from the imaging center, stating:

She calls your office and asks, “What should I do next?”

Breasts are composed of fibrous, glandular, and adipose tissue. If the breasts contain a lot of fibrous and glandular tissue, and little adipose tissue, they are considered to be “dense.” Using mammography, the current standard is to report the density of breast tissue using 4 categories:

Dense breast tissue is defined to include the 2 categories heterogeneously dense and extremely dense.

Observational studies have reported that dense breast tissue is associated with an increased risk of breast cancer, and dense breast tissue makes it more difficult to detect breast cancer on mammography. According to data from the Breast Cancer Surveillance Consortium, among women aged 50 or older, the relative risk of breast cancer stratified by the 4 categories of breast density is 0.59, 1.00, 1.46, and 1.77, for almost entirely fatty, scattered fibroglandular densities, heterogeneously dense, and extremely dense, respectively.¹ In one study, the sensitivity of mammography to detect breast cancer was 82% to 88% for women with nondense breasts and 62% to 69% in women with dense breasts.² These data have catalyzed investigators to explore the use of supplemental imaging to enhance cancer detection in women with dense breasts.

The link between breast density and breast cancer risk and reduced sensitivity of mammography also has catalyzed activists and legislators to champion breast density notification laws, which have passed in more than 20 states. These laws require facilities that perform mammography to notify women with dense breasts that this finding is associated with an increased risk of breast cancer and that dense breasts reduce the ability of mammography to detect cancer. In some states, the law mandates that women with dense breasts be offered supplemental ultrasound imaging and that insurers must cover the cost of the ultrasound studies. Many of the laws recommend that the patient discuss the situation with the clinician who ordered the mammogram.

When I first saw the recommendation for patients to contact me about how to manage dense breasts, my initial response was, “Who? Me?” I felt ill equipped to provide any useful advice and suspected that many of my patients knew more than I about this issue.

Based on a review of the evidence, my current clinical recommendation is outlined in the 2 options below, including a low-resource utilization option and a high-resource utilization option. For patients, physicians, and health systems that are concerned that excessive breast cancer screening tests might cause more harm than benefit, the identification of dense breasts on mammogram is unlikely to be a trigger to perform any additional testing. In this situation, the pragmatic low-resource option is most relevant.

Alternatively, for patients and physicians who strongly believe in the value of screening mammography (see “Utilize tomosynthesis digital mammography technology for your patients” below), a reasonable strategy is to recommend that women with dense breasts and an increased risk for breast cancer be offered supplemental imaging.

In this editorial I elaborate these 2 approaches to breast cancer screening in women with dense breasts.
 

A pragmatic, low-resource utilization screening approach for women with dense breasts
There are no published randomized clinical trials that provide high-quality evidence on what to do if dense breasts are identified on mammography.³ Authors of observational studies have evaluated the potential role of supplemental imaging, including ultrasound and magnetic resonance imaging (MRI), in the management of dense breast tissue (see “Supplemental breast cancer screening modalities” below). Supplemental imaging involves complex trade-offs, balancing the potential benefit of identifying occult early breast cancer lesions not identified by mammography with the risk of subjecting many women without cancer to additional testing and unnecessary biopsies.

A pragmatic, low-resource utilization plan for women with dense breasts involves emphasizing that mammography is the best available screening tool and that annual or biennial mammography is the foundation of all current approaches to breast cancer screening. Supplemental imaging is unnecessary with this approach because there is no evidence that it reduces breast cancer mortality. There is, however, substantial evidence that using supplemental imaging for all women with dense breasts will result in little benefit and great costs, including many unnecessary biopsies.^1,4 Women with dense breasts also could consider annual clinical breast examination.

 

A high-resource utilization screening approach
There are no randomized trials to help guide recommendations about how to respond to a finding of dense breasts on mammography. In addition to breast density, many factors influence breast cancer risk, including a patient’s:

Women with both dense breasts and an increased risk of breast cancer may reap the greatest benefit from supplemental imaging, such as ultrasonography. Therefore, a two-step approach can help.

Step 1: Assess breast cancer risk. This can be accomplished using one of many calculators. Three that are commonly used are the:

The BCSC calculator uses age, race/ethnicity, first-degree relatives with breast cancer, a history of a breast biopsy, and breast density to calculate a 5-year risk of developing breast cancer.

The BCRAT tool uses current age, race/ethnicity, age at menarche, age at first live-birth of a child, number of first-degree relatives with breast cancer, a history of breast biopsies, and the identification of atypical hyperplasia to calculate a 5-year risk of breast cancer.

The IBIS model uses many more variables, including a detailed family history to calculate a 10-year and lifetime risk of breast cancer. If a patient has ductal carcinoma in situ, lobular carcinoma in situ, chest irradiation before age 30 years, or known BRCA1 or BRCA2 mutations, she is instructed not to use the risk calculators because they are at very high risk for breast cancer, and they need an individualized intensive plan for monitoring and prevention (see MRI section in “Supplemental breast cancer screening modalities” above).

Step 2: Use breast density and breast cancer risk to develop a screening plan. The NIH Breast Cancer Surveillance Consortium has published data estimating the risk that a woman with a mammogram negative for cancer will develop breast cancer within the next 12 months (based on her age, breast density, and breast cancer risk—calculated with the BCSC tool).⁸

It reported an increased risk of breast cancer diagnosed within 12 months following a mammogram that was negative for cancer in women with extremely dense breasts and a BCSC 5-year risk of breast cancer of 1.67% or greater and in women with heterogeneously dense breasts and a BCSC 5-year risk of breast cancer of 2.5% or greater.⁸

Using these cutoffs it is estimated that 24% of all women with heterogeneously or extremely dense breasts would be offered supplemental screening with a modality such as ultrasound, and 76% would be guided not to have supplemental screening because their risk of developing breast cancer in the 12 months following their negative mammogram is low.

If this guidance is followed, it would require 694 supplemental ultrasound studies and many biopsies to detect 1 additional breast cancer, significantly increasing overall health care costs.⁸ In many states insurers do not cover supplemental ultrasound imaging of the breasts. In most states insurers require preauthorization for supplemental MRI of the breasts. You need to know the insurance practices in the state to help guide decision making about supplemental imaging. The approach described above is consistent with the American College of Obstetricians and Gynecologists recommendation that women with dense breasts, who are asymptomaticand have no additional risk factors for breast cancer, do not need to be offered supplemental imaging.⁹

Case: Next steps
The BCSC calculator reveals that the 51-year-old woman with a family history of breast cancer and a mammogram showing extremely dense breasts has a 5-year risk of breast cancer of 2.68%. Given that this risk is elevated, this patient could be offered supplemental ultrasound screening and annual breast clinical examination. In addition, she could be further counseled about breast cancer chemoprevention options.¹⁰

Women with a strong family history of breast and/or ovarian cancer also could be referred for genetic counseling and BRCA testing.¹¹ The risk of having a BRCA mutation can be calculated using the BRCAPRO tool.¹²

Most women with dense breast tissue on mammography will never develop breast cancer. Yet the presence of dense breast tissue both increases the risk of breast cancer and decreases the sensitivity of mammography to detect cancer. There are no high-quality data from randomized trials to help guide our recommendations concerning the management of dense breasts identified on mammography. Yet many states have laws that suggest patients ask you to provide advice about breast density.

Patients, clinicians, and health systems vary in their confidence in the clinical value of breast cancer screening programs. Consequently, there is no “right answer” to this vexing problem. The standard of care is to support a range of options tailored to the specific clinical characteristics and needs of each patient. 
 

Some psychiatrists are rapid adopt­ers of the latest discoveries. Others wait before they adopt new modalities and change their practice accordingly. Then, there are some—admittedly, a minority—who stubbornly persist in practicing exactly as they did 30 or 40 years ago when they completed residency.

What are the foundations of exemplary, advanced, brain-based psychiatric care?
Here are my 10 proposed tenets of excel­lence in psychiatric practice. They reflect superior assessment and management of patients as well as personal growth and contributions to the specialty.

Provide a complete medical assess­ment for every patient at the first lifetime psychiatric contact, whether inpatient or outpatient. This includes routine physical and neurologic exami­nations and a panel of basic laboratory tests (complete blood count, liver and kidney functions, urine screen, thyroid-stimulating hormone, electrolytes, fast­ing glucose, and fasting lipids). All vital signs are measured and recorded. Referrals to other medical specialists are made as needed.

This medical assessment must, of course, include a comprehensive psy­chiatric evaluation: personal history, social history, medical history, family history, and a complete neuropsychiat­ric mental status examination.

Create a thorough 3-generation pedigree of all relatives, indicating not only psychopathology, addiction, and legal problems but also medical (espe­cially neurologic) disorders and cause of death.

Perform basic assessment of brain structure and function (a MRI scan, a neurocognitive battery, and tests of neu­rologic soft signs).

Measure biomarkers that reflect potential harm to the brain according to emerging research—eg, pro-inflam­matory markers (such as C-reactive protein [CRP], interleukin-6, and tumor necrosis factor alpha [TNF-α]) and oxidative stress biomarkers of increased free radical activity (super­oxide dismutase [SOD], glutathione, thiobarbituric acid [GSH] reactive sub­stances [TBARS], and catalase).

Maintain measurement-based prac­tice, in which:
   • severity of illness is measured by a specific, appropriate rating scale (eg, Positive and Negative Syndrome Scale for schizophre­nia [PANSS], Young Mania Rating Scale [YMRS], Montgomery-Åsberg Depression Rating Scale [MADRS] for depression, Hamilton Anxiety Rating Scale [HAM-A] for anxiety, Yale-Brown Obsessive Compulsive Scale [Y-BOCS] for obsessions and compulsions)
   • degree of response to treatment is measured as a reflection of the extent of drop in the total score of those rat­ing scales, which are administered at every visit
   • severity of common side effects is measured by the Simpson-Angus Scale (SAS) for parkinsonism, the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia, the Glasgow Antipsychotic Side-effect Scale (GASS), etc.

Use tier-1 evidence-based psychiatry (that is, findings from large, placebo-controlled, double-blind studies) to select best treatments. This includes being familiar with:
   • principles of meta-analysis
   • the meaning of low, medium, and large effect sizes
   • for every medication used, the calculation and clinical implications of number needed to treat (NNT) and num­ber needed to harm (NNH).

Always combine the dual manage­ment approaches of pharmacother­apy plus psychotherapy/psychosocial therapy.

Share knowledge and experience gleaned from practice with the commu­nity of psychiatrists, including:
   • writing letters to the editor about a clinical matter
   • submitting case reports or case series for publication
   • teaching students or residents at the local medical school (after obtaining adjunct faculty status).

In addition, psychiatrists should educate the public to eliminate misper­ceptions and erase stigma about mental illness.

Participate in creating new psychiat­ric knowledge by developing skills to become a clinical trialist, so that you can participate as an investigator in multi­center clinical trials of new medications, or, at least, refer patients for possible participation in ongoing clinical trials conducted at local academic centers.

Engage in effective and continuous life-learning, by:
   • attending weekly Grand Rounds at the nearest academic department of psychiatry
   • attending national continu­ing medical education conferences annually
   • scanning PubMed regularly (at least 3 times a week, if not daily) for the latest research related to one’s patients or to read about advances in one’s clini­cal subspecialty; read the abstracts and download several PDFs a week for subsequent reading.

Some readers will agree with part, but not all, of these proposed compo­nents of advanced psychiatric practice. That’s to be expected; I welcome your letters rebutting some tenets, or propos­ing additional ones, of a sophisticated psychiatric practice. After all, sophisti­cation is a journey, not a destination.

Some psychiatrists are rapid adopt­ers of the latest discoveries. Others wait before they adopt new modalities and change their practice accordingly. Then, there are some—admittedly, a minority—who stubbornly persist in practicing exactly as they did 30 or 40 years ago when they completed residency.

What are the foundations of exemplary, advanced, brain-based psychiatric care?
Here are my 10 proposed tenets of excel­lence in psychiatric practice. They reflect superior assessment and management of patients as well as personal growth and contributions to the specialty.

Provide a complete medical assess­ment for every patient at the first lifetime psychiatric contact, whether inpatient or outpatient. This includes routine physical and neurologic exami­nations and a panel of basic laboratory tests (complete blood count, liver and kidney functions, urine screen, thyroid-stimulating hormone, electrolytes, fast­ing glucose, and fasting lipids). All vital signs are measured and recorded. Referrals to other medical specialists are made as needed.

This medical assessment must, of course, include a comprehensive psy­chiatric evaluation: personal history, social history, medical history, family history, and a complete neuropsychiat­ric mental status examination.

Create a thorough 3-generation pedigree of all relatives, indicating not only psychopathology, addiction, and legal problems but also medical (espe­cially neurologic) disorders and cause of death.

Perform basic assessment of brain structure and function (a MRI scan, a neurocognitive battery, and tests of neu­rologic soft signs).

Measure biomarkers that reflect potential harm to the brain according to emerging research—eg, pro-inflam­matory markers (such as C-reactive protein [CRP], interleukin-6, and tumor necrosis factor alpha [TNF-α]) and oxidative stress biomarkers of increased free radical activity (super­oxide dismutase [SOD], glutathione, thiobarbituric acid [GSH] reactive sub­stances [TBARS], and catalase).

Maintain measurement-based prac­tice, in which:
   • severity of illness is measured by a specific, appropriate rating scale (eg, Positive and Negative Syndrome Scale for schizophre­nia [PANSS], Young Mania Rating Scale [YMRS], Montgomery-Åsberg Depression Rating Scale [MADRS] for depression, Hamilton Anxiety Rating Scale [HAM-A] for anxiety, Yale-Brown Obsessive Compulsive Scale [Y-BOCS] for obsessions and compulsions)
   • degree of response to treatment is measured as a reflection of the extent of drop in the total score of those rat­ing scales, which are administered at every visit
   • severity of common side effects is measured by the Simpson-Angus Scale (SAS) for parkinsonism, the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia, the Glasgow Antipsychotic Side-effect Scale (GASS), etc.

Use tier-1 evidence-based psychiatry (that is, findings from large, placebo-controlled, double-blind studies) to select best treatments. This includes being familiar with:
   • principles of meta-analysis
   • the meaning of low, medium, and large effect sizes
   • for every medication used, the calculation and clinical implications of number needed to treat (NNT) and num­ber needed to harm (NNH).

Always combine the dual manage­ment approaches of pharmacother­apy plus psychotherapy/psychosocial therapy.

Share knowledge and experience gleaned from practice with the commu­nity of psychiatrists, including:
   • writing letters to the editor about a clinical matter
   • submitting case reports or case series for publication
   • teaching students or residents at the local medical school (after obtaining adjunct faculty status).

In addition, psychiatrists should educate the public to eliminate misper­ceptions and erase stigma about mental illness.

Participate in creating new psychiat­ric knowledge by developing skills to become a clinical trialist, so that you can participate as an investigator in multi­center clinical trials of new medications, or, at least, refer patients for possible participation in ongoing clinical trials conducted at local academic centers.

Engage in effective and continuous life-learning, by:
   • attending weekly Grand Rounds at the nearest academic department of psychiatry
   • attending national continu­ing medical education conferences annually
   • scanning PubMed regularly (at least 3 times a week, if not daily) for the latest research related to one’s patients or to read about advances in one’s clini­cal subspecialty; read the abstracts and download several PDFs a week for subsequent reading.

Some readers will agree with part, but not all, of these proposed compo­nents of advanced psychiatric practice. That’s to be expected; I welcome your letters rebutting some tenets, or propos­ing additional ones, of a sophisticated psychiatric practice. After all, sophisti­cation is a journey, not a destination.

Some psychiatrists are rapid adopt­ers of the latest discoveries. Others wait before they adopt new modalities and change their practice accordingly. Then, there are some—admittedly, a minority—who stubbornly persist in practicing exactly as they did 30 or 40 years ago when they completed residency.

What are the foundations of exemplary, advanced, brain-based psychiatric care?
Here are my 10 proposed tenets of excel­lence in psychiatric practice. They reflect superior assessment and management of patients as well as personal growth and contributions to the specialty.

Provide a complete medical assess­ment for every patient at the first lifetime psychiatric contact, whether inpatient or outpatient. This includes routine physical and neurologic exami­nations and a panel of basic laboratory tests (complete blood count, liver and kidney functions, urine screen, thyroid-stimulating hormone, electrolytes, fast­ing glucose, and fasting lipids). All vital signs are measured and recorded. Referrals to other medical specialists are made as needed.

This medical assessment must, of course, include a comprehensive psy­chiatric evaluation: personal history, social history, medical history, family history, and a complete neuropsychiat­ric mental status examination.

Create a thorough 3-generation pedigree of all relatives, indicating not only psychopathology, addiction, and legal problems but also medical (espe­cially neurologic) disorders and cause of death.

Perform basic assessment of brain structure and function (a MRI scan, a neurocognitive battery, and tests of neu­rologic soft signs).

Measure biomarkers that reflect potential harm to the brain according to emerging research—eg, pro-inflam­matory markers (such as C-reactive protein [CRP], interleukin-6, and tumor necrosis factor alpha [TNF-α]) and oxidative stress biomarkers of increased free radical activity (super­oxide dismutase [SOD], glutathione, thiobarbituric acid [GSH] reactive sub­stances [TBARS], and catalase).

Maintain measurement-based prac­tice, in which:
   • severity of illness is measured by a specific, appropriate rating scale (eg, Positive and Negative Syndrome Scale for schizophre­nia [PANSS], Young Mania Rating Scale [YMRS], Montgomery-Åsberg Depression Rating Scale [MADRS] for depression, Hamilton Anxiety Rating Scale [HAM-A] for anxiety, Yale-Brown Obsessive Compulsive Scale [Y-BOCS] for obsessions and compulsions)
   • degree of response to treatment is measured as a reflection of the extent of drop in the total score of those rat­ing scales, which are administered at every visit
   • severity of common side effects is measured by the Simpson-Angus Scale (SAS) for parkinsonism, the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia, the Glasgow Antipsychotic Side-effect Scale (GASS), etc.

Use tier-1 evidence-based psychiatry (that is, findings from large, placebo-controlled, double-blind studies) to select best treatments. This includes being familiar with:
   • principles of meta-analysis
   • the meaning of low, medium, and large effect sizes
   • for every medication used, the calculation and clinical implications of number needed to treat (NNT) and num­ber needed to harm (NNH).

Always combine the dual manage­ment approaches of pharmacother­apy plus psychotherapy/psychosocial therapy.

Share knowledge and experience gleaned from practice with the commu­nity of psychiatrists, including:
   • writing letters to the editor about a clinical matter
   • submitting case reports or case series for publication
   • teaching students or residents at the local medical school (after obtaining adjunct faculty status).

In addition, psychiatrists should educate the public to eliminate misper­ceptions and erase stigma about mental illness.

Participate in creating new psychiat­ric knowledge by developing skills to become a clinical trialist, so that you can participate as an investigator in multi­center clinical trials of new medications, or, at least, refer patients for possible participation in ongoing clinical trials conducted at local academic centers.

Engage in effective and continuous life-learning, by:
   • attending weekly Grand Rounds at the nearest academic department of psychiatry
   • attending national continu­ing medical education conferences annually
   • scanning PubMed regularly (at least 3 times a week, if not daily) for the latest research related to one’s patients or to read about advances in one’s clini­cal subspecialty; read the abstracts and download several PDFs a week for subsequent reading.

Some readers will agree with part, but not all, of these proposed compo­nents of advanced psychiatric practice. That’s to be expected; I welcome your letters rebutting some tenets, or propos­ing additional ones, of a sophisticated psychiatric practice. After all, sophisti­cation is a journey, not a destination.

In a report of a study that was published recently in a top-tier psychiatry journal,¹ researchers describe a stunning finding that challenges the notion that there is a plethora of psychiatric brain disorders. They conducted a large meta-analysis of 193 published brain imaging studies of people with schizophrenia, bipolar disorder, major depression, obsessive-compulsive disorder (OCD), anxiety, and addiction. They found that those 6 supposedly discrete illnesses are all associated with a varying degree of shrinkage (atrophy or hypoplasia) of the same 3 brain regions:
   • Dorsal anterior cingulate cortex. This region around the frontal part of the corpus callosum controls rational cogni­tive processes, reward anticipation, deci­sion making, empathy, impulse control, and emotional response. Francis Crick, the Nobel laureate who first described the structure of DNA, hypothesized that the anterior cingulate sulcus might even be the center of what we call “free will.”
   • Left insula and right insula. The insulae are the cortical regions deep inside the lateral sulcus, which is the fissure that separates the temporal lobe from the parietal and frontal lobes. The functions of the insulae include consciousness, emotions, perceptions, motor control, self-awareness, cognitive functioning, and interpersonal experi­ence. (In addicts, the insular cortex is activated when they are exposed to environmental cues that trigger craving because the insulae are a target for the dopamine system. Notably, it has been reported that, when cigarette addicts suffer a stroke that damages the insulae, they stop smoking completely.)

The 3 regions of the brain, in which pathology extends across 6 DSM-5 diagnoses, work together to manage high-level executive functions, such as working memory, reasoning, and flex­ible thinking. The degree of dysfunction varies among the 6 clinical disorders, with schizophrenia having the highest severity.

Neurobiological commonality
The idea of shared neurobiological underpinnings among 6 distinct psy­chiatric disorders flies in the face of the entrenched DSM model, in which those 6 disorders are distinct disease entities. Other studies (including the Bipolar Schizophrenia Network on Intermediate Phenotypes) also found prominent biological similarities in varying degrees across schizophrenia, schizoaffective disorder, and bipo­lar disorder.^2,3 The Research Domain Criteria of the National Institute of Mental Health also embraces the dimensional approach to neurobio­logical biomarkers across various psy­chiatric disorders.

A common genetic substrate also is emerging. A recently published genome-wide association study, con­ducted on 33,332 psychiatric patients and 27,888 controls,⁴ revealed that a number of genes are shared by 5 differ­ent psychiatric disorders: schizophre­nia, autism, bipolar disorder, major depression, and attention-deficit/hyperactivity disorder. The genetic phenomenon of the same genes mani­festing in different clinical phenotypes is called pleiotropy, and is consistent with shared neurobiological findings.

Genetic and brain structural com­monalities among multiple DSM diag­nostic categories might explain some well-known clinical observations:
   • frequent comorbidity of certain psychiatric disorders, such as depres­sion and addiction in schizophrenia; anxiety and OCD in bipolar disorder; depression with OCD and addictions; and so on
   • the presence of intermediate phe­notypes in unaffected family mem­bers, such as cognitive dysfunction in the parents of patients with schizo­phrenia, compared with parents of matched healthy controls⁵
   • the much higher rate of psycho­pathology among family members of patients with a major psychiatric disorder, compared with the general population.⁶

Core inflexible thinking. So what about clinical features across those disorders that share genetic and neu­robiologic similarities? Psychiatrists may agree that symptoms of schizo­phrenia, bipolar disorder, major depression, OCD, anxiety, and addic­tion appear very different. However, given that reasoning and flexible thinking are functions of the insulae, which are shrunken in all 6 disor­ders, one can postulate that inflexible thinking (fixed false beliefs also are called psychotic delusions) might be a common feature across all those dis­orders. Namely:
   • schizophrenia is known for para­noid or implausible delusions
   • bipolar disorder is characterized by grandiose delusions
   • major depressive disorder is associated with a fixed false belief of worthlessness as well as hopelessness
   • anxiety patients harbor the fixed false belief of impending doom or death (the plane will crash if they are a passenger on it)
   • OCD manifests as ego-dystonic false beliefs (obsessions) that can progress into ego-syntonic delusions
   • people with an alcohol or tobacco addiction are in delusional denial that they are not really addicted or that they will not be harmed by their drug of abuse. Pathologic gamblers harbor the false belief that they will soon reverse their fortunes and “win big.”

It seems that poor reality testing and impaired reasoning is a common feature of not only all 6 psychiatric disorders with shared neurobiology, but others, too, including anorexia nervosa, body dysmorphic disorder, delirium, and dementia.

From a thick volume to… a booklet?
Can you envision a day when psychiat­ric disorders are conceptualized as hav­ing a common genetic, neurobiological, and clinical core, with some variability in phenotype and behavior? If further brain research steers psychiatric nosology in that direction, we might end up with a DSM of 10 pages instead of almost 1,000, with an “Appendix” of genetic, neuroim­aging, and other emerging biomarkers.

Bold scientific prophecies often sound delusional—until they come true….

In a report of a study that was published recently in a top-tier psychiatry journal,¹ researchers describe a stunning finding that challenges the notion that there is a plethora of psychiatric brain disorders. They conducted a large meta-analysis of 193 published brain imaging studies of people with schizophrenia, bipolar disorder, major depression, obsessive-compulsive disorder (OCD), anxiety, and addiction. They found that those 6 supposedly discrete illnesses are all associated with a varying degree of shrinkage (atrophy or hypoplasia) of the same 3 brain regions:
   • Dorsal anterior cingulate cortex. This region around the frontal part of the corpus callosum controls rational cogni­tive processes, reward anticipation, deci­sion making, empathy, impulse control, and emotional response. Francis Crick, the Nobel laureate who first described the structure of DNA, hypothesized that the anterior cingulate sulcus might even be the center of what we call “free will.”
   • Left insula and right insula. The insulae are the cortical regions deep inside the lateral sulcus, which is the fissure that separates the temporal lobe from the parietal and frontal lobes. The functions of the insulae include consciousness, emotions, perceptions, motor control, self-awareness, cognitive functioning, and interpersonal experi­ence. (In addicts, the insular cortex is activated when they are exposed to environmental cues that trigger craving because the insulae are a target for the dopamine system. Notably, it has been reported that, when cigarette addicts suffer a stroke that damages the insulae, they stop smoking completely.)

The 3 regions of the brain, in which pathology extends across 6 DSM-5 diagnoses, work together to manage high-level executive functions, such as working memory, reasoning, and flex­ible thinking. The degree of dysfunction varies among the 6 clinical disorders, with schizophrenia having the highest severity.

Neurobiological commonality
The idea of shared neurobiological underpinnings among 6 distinct psy­chiatric disorders flies in the face of the entrenched DSM model, in which those 6 disorders are distinct disease entities. Other studies (including the Bipolar Schizophrenia Network on Intermediate Phenotypes) also found prominent biological similarities in varying degrees across schizophrenia, schizoaffective disorder, and bipo­lar disorder.^2,3 The Research Domain Criteria of the National Institute of Mental Health also embraces the dimensional approach to neurobio­logical biomarkers across various psy­chiatric disorders.

A common genetic substrate also is emerging. A recently published genome-wide association study, con­ducted on 33,332 psychiatric patients and 27,888 controls,⁴ revealed that a number of genes are shared by 5 differ­ent psychiatric disorders: schizophre­nia, autism, bipolar disorder, major depression, and attention-deficit/hyperactivity disorder. The genetic phenomenon of the same genes mani­festing in different clinical phenotypes is called pleiotropy, and is consistent with shared neurobiological findings.

Genetic and brain structural com­monalities among multiple DSM diag­nostic categories might explain some well-known clinical observations:
   • frequent comorbidity of certain psychiatric disorders, such as depres­sion and addiction in schizophrenia; anxiety and OCD in bipolar disorder; depression with OCD and addictions; and so on
   • the presence of intermediate phe­notypes in unaffected family mem­bers, such as cognitive dysfunction in the parents of patients with schizo­phrenia, compared with parents of matched healthy controls⁵
   • the much higher rate of psycho­pathology among family members of patients with a major psychiatric disorder, compared with the general population.⁶

Core inflexible thinking. So what about clinical features across those disorders that share genetic and neu­robiologic similarities? Psychiatrists may agree that symptoms of schizo­phrenia, bipolar disorder, major depression, OCD, anxiety, and addic­tion appear very different. However, given that reasoning and flexible thinking are functions of the insulae, which are shrunken in all 6 disor­ders, one can postulate that inflexible thinking (fixed false beliefs also are called psychotic delusions) might be a common feature across all those dis­orders. Namely:
   • schizophrenia is known for para­noid or implausible delusions
   • bipolar disorder is characterized by grandiose delusions
   • major depressive disorder is associated with a fixed false belief of worthlessness as well as hopelessness
   • anxiety patients harbor the fixed false belief of impending doom or death (the plane will crash if they are a passenger on it)
   • OCD manifests as ego-dystonic false beliefs (obsessions) that can progress into ego-syntonic delusions
   • people with an alcohol or tobacco addiction are in delusional denial that they are not really addicted or that they will not be harmed by their drug of abuse. Pathologic gamblers harbor the false belief that they will soon reverse their fortunes and “win big.”

It seems that poor reality testing and impaired reasoning is a common feature of not only all 6 psychiatric disorders with shared neurobiology, but others, too, including anorexia nervosa, body dysmorphic disorder, delirium, and dementia.

From a thick volume to… a booklet?
Can you envision a day when psychiat­ric disorders are conceptualized as hav­ing a common genetic, neurobiological, and clinical core, with some variability in phenotype and behavior? If further brain research steers psychiatric nosology in that direction, we might end up with a DSM of 10 pages instead of almost 1,000, with an “Appendix” of genetic, neuroim­aging, and other emerging biomarkers.

Bold scientific prophecies often sound delusional—until they come true….

In a report of a study that was published recently in a top-tier psychiatry journal,¹ researchers describe a stunning finding that challenges the notion that there is a plethora of psychiatric brain disorders. They conducted a large meta-analysis of 193 published brain imaging studies of people with schizophrenia, bipolar disorder, major depression, obsessive-compulsive disorder (OCD), anxiety, and addiction. They found that those 6 supposedly discrete illnesses are all associated with a varying degree of shrinkage (atrophy or hypoplasia) of the same 3 brain regions:
   • Dorsal anterior cingulate cortex. This region around the frontal part of the corpus callosum controls rational cogni­tive processes, reward anticipation, deci­sion making, empathy, impulse control, and emotional response. Francis Crick, the Nobel laureate who first described the structure of DNA, hypothesized that the anterior cingulate sulcus might even be the center of what we call “free will.”
   • Left insula and right insula. The insulae are the cortical regions deep inside the lateral sulcus, which is the fissure that separates the temporal lobe from the parietal and frontal lobes. The functions of the insulae include consciousness, emotions, perceptions, motor control, self-awareness, cognitive functioning, and interpersonal experi­ence. (In addicts, the insular cortex is activated when they are exposed to environmental cues that trigger craving because the insulae are a target for the dopamine system. Notably, it has been reported that, when cigarette addicts suffer a stroke that damages the insulae, they stop smoking completely.)

The 3 regions of the brain, in which pathology extends across 6 DSM-5 diagnoses, work together to manage high-level executive functions, such as working memory, reasoning, and flex­ible thinking. The degree of dysfunction varies among the 6 clinical disorders, with schizophrenia having the highest severity.

Neurobiological commonality
The idea of shared neurobiological underpinnings among 6 distinct psy­chiatric disorders flies in the face of the entrenched DSM model, in which those 6 disorders are distinct disease entities. Other studies (including the Bipolar Schizophrenia Network on Intermediate Phenotypes) also found prominent biological similarities in varying degrees across schizophrenia, schizoaffective disorder, and bipo­lar disorder.^2,3 The Research Domain Criteria of the National Institute of Mental Health also embraces the dimensional approach to neurobio­logical biomarkers across various psy­chiatric disorders.

A common genetic substrate also is emerging. A recently published genome-wide association study, con­ducted on 33,332 psychiatric patients and 27,888 controls,⁴ revealed that a number of genes are shared by 5 differ­ent psychiatric disorders: schizophre­nia, autism, bipolar disorder, major depression, and attention-deficit/hyperactivity disorder. The genetic phenomenon of the same genes mani­festing in different clinical phenotypes is called pleiotropy, and is consistent with shared neurobiological findings.

Genetic and brain structural com­monalities among multiple DSM diag­nostic categories might explain some well-known clinical observations:
   • frequent comorbidity of certain psychiatric disorders, such as depres­sion and addiction in schizophrenia; anxiety and OCD in bipolar disorder; depression with OCD and addictions; and so on
   • the presence of intermediate phe­notypes in unaffected family mem­bers, such as cognitive dysfunction in the parents of patients with schizo­phrenia, compared with parents of matched healthy controls⁵
   • the much higher rate of psycho­pathology among family members of patients with a major psychiatric disorder, compared with the general population.⁶

Core inflexible thinking. So what about clinical features across those disorders that share genetic and neu­robiologic similarities? Psychiatrists may agree that symptoms of schizo­phrenia, bipolar disorder, major depression, OCD, anxiety, and addic­tion appear very different. However, given that reasoning and flexible thinking are functions of the insulae, which are shrunken in all 6 disor­ders, one can postulate that inflexible thinking (fixed false beliefs also are called psychotic delusions) might be a common feature across all those dis­orders. Namely:
   • schizophrenia is known for para­noid or implausible delusions
   • bipolar disorder is characterized by grandiose delusions
   • major depressive disorder is associated with a fixed false belief of worthlessness as well as hopelessness
   • anxiety patients harbor the fixed false belief of impending doom or death (the plane will crash if they are a passenger on it)
   • OCD manifests as ego-dystonic false beliefs (obsessions) that can progress into ego-syntonic delusions
   • people with an alcohol or tobacco addiction are in delusional denial that they are not really addicted or that they will not be harmed by their drug of abuse. Pathologic gamblers harbor the false belief that they will soon reverse their fortunes and “win big.”

It seems that poor reality testing and impaired reasoning is a common feature of not only all 6 psychiatric disorders with shared neurobiology, but others, too, including anorexia nervosa, body dysmorphic disorder, delirium, and dementia.

From a thick volume to… a booklet?
Can you envision a day when psychiat­ric disorders are conceptualized as hav­ing a common genetic, neurobiological, and clinical core, with some variability in phenotype and behavior? If further brain research steers psychiatric nosology in that direction, we might end up with a DSM of 10 pages instead of almost 1,000, with an “Appendix” of genetic, neuroim­aging, and other emerging biomarkers.

Bold scientific prophecies often sound delusional—until they come true….

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For the past 60 years, the standard of care has remained one-dimensional in this brain syndrome, even though the clini­cal and neurobiological complexities of schizophrenia are multidimensional. Dopamine D2 receptor antagonists, dis­covered serendipitously in the 1950s, have remained the mainstay of treat­ment, despite momentous insights about the neurodevelopmental and neurode­generative processes of schizophrenia.

Why do we ignore abundant evi­dence that the brain in schizophrenia needs extensive structural repair, not simply a reduction in the activity of a single neurotransmitter in the mesolim­bic dopamine tract? Perhaps the age-old dogmatic pessimism that neurodegen­eration cannot be reversed has inhibited the field from attempting to escape the dopamine box, so to speak, and from developing innovative, even radical, approaches to repair of the brain of per­sons with schizophrenia.

But radical thinking is justified when dealing with a cruel brain syndrome that disables young adults in the prime of life.

We should exploit neuroprotective tactics
Several neuroprotective approaches to preventing or reversing the degen­erative changes across brain regions in schizophrenia are now recognized. Indirect evidence exists for such inter­ventions in animal models, but the results of few controlled human studies have been published.

Here are my proposals for using neuroprotective tactics to address the unmet need to repair the brain of patients ravaged by neurotoxic psy­chotic relapses.

Promote 100% adherence to anti­psychotic therapy. The simplest tac­tic to protect the brain from atrophy in patients with schizophrenia is to use long-acting injectable antipsychotic agents immediately after the first psy­chotic episode. The risk of a psychotic relapse is far lower (7-fold lower, according to a study performed at the University of California, Los Angeles, that soon will be published) with an injectable medication than with oral medication in first-episode patients. Preventing psychotic episodes is, logi­cally, the most important neuroprotec­tive tactic.

Enhance neurogenesis. The brain has 2 neurogenic regions that produce pro­genitor cells (stem cells) that gradually mature and differentiate into neurons and glia. That is how the brain naturally replenishes itself throughout life. This adult neurogenesis process, carried out in the dentate gyrus of the hippocam­pus and in the subventricular zone, stops during psychosis but resumes when psychosis remits.

Second-generation antipsychotics (but not first-generation agents) stimulate neurogenesis in animals.¹ Haloperidol, in fact, does the opposite—suppressing neurogenesis and causing neuronal death via 15 different molecular mechanisms (see my editorial, “Haloperidol clearly is neurotoxic. Should it be banned?,” in the July 2013 issue).

Other psychotropics also induce neurogenesis, including selective serotonin reuptake inhibitors (SSRIs), which increase hippocampal neurogen­esis (atypical antipsychotics appear to increase neurogenesis in the subventric­ular zone).² SSRIs often have been used in schizophrenia patients for 2 common comorbid conditions: depression and anxiety. These agents can help regener­ate brain tissue, in addition to providing their approved therapeutic indications.

Lithium and valproate have been shown to be neuroprotective³ and to stimulate neurogenesis. Both are often used in schizoaffective disorder, bipolar type; they can exert a neuroprotective effect in addition to their clinical use­fulness. The combination of an SSRI or lithium with a second-generation anti­psychotic could be synergistic in tur­bocharging neurogenesis. This sounds like polypharmacy—but it is a rational approach that deserves to be put to the test.

Increase neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). When neurotrophin levels decline, the brain starts shrinking because of apoptosis. Psychosis lowers neurotrophins drasti­cally—by approximately 60%. Atypical antipsychotics have been reported to increase the level of neurotrophins; hal­operidol actually lowers those levels.⁴

Decrease inflammation. Psychosis has been shown to be associated with neuro-inflammation, as reflected in a surge of pro-inflammatory cytokines (released from activated microglia).⁵ A rise in interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and other pro-inflammatory markers has been extensively documented in many studies.

With that observed rise in mind, sev­eral controlled studies have shown that adding an anti-inflammatory agent (aspi­rin, a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or minocycline) to an antipsychotic can accentuate the therapeutic response, especially during a first episode of psychosis.⁶ Note also that second-generation antipsychotics have anti-inflammatory effects⁷ as well that might be part of their efficacy beyond blocking dopamine D2 receptors.

Decrease free radicals. Microglia are activated by psychosis to release free radicals, also known as reactive oxygen species; these include nitric oxide, super­oxide, and peroxynitrate. All these spe­cies are destructive to brain tissue. Using an adjunctive strong antioxidant, such as N-acetyl cysteine,⁸ with an antipsychotic might help neutralize destructive effects of free radicals and protect the brain from tissue loss during a psychotic episode.

Avoid apoptosis inducers. Several sub­stances can initiate programmed cell death (apoptosis), which is triggered during psychosis (believed to be caused by increased dopamine and, possibly, glutamate, activity) and which leads to brain atrophy. Patients with schizophre­nia must be protected from these apop­tosis inducers:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

Apoptosis can be inhibited by main­taining high levels of neurotrophic factors. Atypical, but not typical, anti­psychotics increase levels of neuro­trophins, such as NGF and BDNF.⁴ In addition, the Bcl-2 family of proteins inhibits apoptosis,⁹ and drugs such as lithium and valproate can induce Bcl-2 and protect against apoptosis and neu­ronal loss.³

Restore white-matter integrity. Numerous studies using diffusion ten­sor imaging have revealed that myelin is reduced or lacks integrity in schizophre­nia. This results in loss of critical connec­tivity among brain regions, which might explain psychotic and cognitive symp­toms. One possible way to repair white matter, which becomes more damaged after multiple psychotic episodes, is to use drugs indicated to treat the demy­elinating disorder multiple sclerosis. Antagonists of LINGO-1, a negative regulator of axonal myelination, are a prominent possibility; a recent study reported altered signaling of LINGO-1 in schizophrenia.¹⁰

Decrease excessive glutamate. Because glutamate is neurotoxic and might contribute to brain-tissue loss during psychosis, it is important to reduce glutamate activity in schizophre­nia. Lamotrigine and valproate are both known to do that.¹¹ Several studies indi­cate that adjunctive lamotrigine might be helpful in schizophrenia.¹²

Inhibit caspase-3, also known as the “death cascade,” which is involved in brain-tissue loss. Eicosapentaenoic acid is an omega-3 fatty acid that inhibits caspase-3. Interestingly, omega-3 levels in patients with schizophrenia are signif­icantly lower than in healthy subjects.13 Lithium also can inhibit caspase-3.

Do these proposals sound radical?
Most of the recommendations I’ve made here are not employed in the clinical prac­tice of psychiatry. These ideas must be put to the test in controlled clinical trials.

The crux of my argument is that we need to think outside the “dopamine box” and focus on brain repair if we are to make progress in reversing, even pre­venting, neurodegeneration and clini­cal deterioration in this disabling brain syndrome. Just as cancer often is treated with rational polypharmacy, schizo­phrenia might need a similar approach. To vanquish schizophrenia—a goal that has eluded us—it is imperative to pur­sue radically novel and disruptive ther­apeutic strategies. The ideas I’ve listed here sound the call that the quest to repair the brain in schizophrenia must begin, and soon.

For the past 60 years, the standard of care has remained one-dimensional in this brain syndrome, even though the clini­cal and neurobiological complexities of schizophrenia are multidimensional. Dopamine D2 receptor antagonists, dis­covered serendipitously in the 1950s, have remained the mainstay of treat­ment, despite momentous insights about the neurodevelopmental and neurode­generative processes of schizophrenia.

Why do we ignore abundant evi­dence that the brain in schizophrenia needs extensive structural repair, not simply a reduction in the activity of a single neurotransmitter in the mesolim­bic dopamine tract? Perhaps the age-old dogmatic pessimism that neurodegen­eration cannot be reversed has inhibited the field from attempting to escape the dopamine box, so to speak, and from developing innovative, even radical, approaches to repair of the brain of per­sons with schizophrenia.

But radical thinking is justified when dealing with a cruel brain syndrome that disables young adults in the prime of life.

We should exploit neuroprotective tactics
Several neuroprotective approaches to preventing or reversing the degen­erative changes across brain regions in schizophrenia are now recognized. Indirect evidence exists for such inter­ventions in animal models, but the results of few controlled human studies have been published.

Here are my proposals for using neuroprotective tactics to address the unmet need to repair the brain of patients ravaged by neurotoxic psy­chotic relapses.

Promote 100% adherence to anti­psychotic therapy. The simplest tac­tic to protect the brain from atrophy in patients with schizophrenia is to use long-acting injectable antipsychotic agents immediately after the first psy­chotic episode. The risk of a psychotic relapse is far lower (7-fold lower, according to a study performed at the University of California, Los Angeles, that soon will be published) with an injectable medication than with oral medication in first-episode patients. Preventing psychotic episodes is, logi­cally, the most important neuroprotec­tive tactic.

Enhance neurogenesis. The brain has 2 neurogenic regions that produce pro­genitor cells (stem cells) that gradually mature and differentiate into neurons and glia. That is how the brain naturally replenishes itself throughout life. This adult neurogenesis process, carried out in the dentate gyrus of the hippocam­pus and in the subventricular zone, stops during psychosis but resumes when psychosis remits.

Second-generation antipsychotics (but not first-generation agents) stimulate neurogenesis in animals.¹ Haloperidol, in fact, does the opposite—suppressing neurogenesis and causing neuronal death via 15 different molecular mechanisms (see my editorial, “Haloperidol clearly is neurotoxic. Should it be banned?,” in the July 2013 issue).

Other psychotropics also induce neurogenesis, including selective serotonin reuptake inhibitors (SSRIs), which increase hippocampal neurogen­esis (atypical antipsychotics appear to increase neurogenesis in the subventric­ular zone).² SSRIs often have been used in schizophrenia patients for 2 common comorbid conditions: depression and anxiety. These agents can help regener­ate brain tissue, in addition to providing their approved therapeutic indications.

Lithium and valproate have been shown to be neuroprotective³ and to stimulate neurogenesis. Both are often used in schizoaffective disorder, bipolar type; they can exert a neuroprotective effect in addition to their clinical use­fulness. The combination of an SSRI or lithium with a second-generation anti­psychotic could be synergistic in tur­bocharging neurogenesis. This sounds like polypharmacy—but it is a rational approach that deserves to be put to the test.

Increase neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). When neurotrophin levels decline, the brain starts shrinking because of apoptosis. Psychosis lowers neurotrophins drasti­cally—by approximately 60%. Atypical antipsychotics have been reported to increase the level of neurotrophins; hal­operidol actually lowers those levels.⁴

Decrease inflammation. Psychosis has been shown to be associated with neuro-inflammation, as reflected in a surge of pro-inflammatory cytokines (released from activated microglia).⁵ A rise in interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and other pro-inflammatory markers has been extensively documented in many studies.

With that observed rise in mind, sev­eral controlled studies have shown that adding an anti-inflammatory agent (aspi­rin, a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or minocycline) to an antipsychotic can accentuate the therapeutic response, especially during a first episode of psychosis.⁶ Note also that second-generation antipsychotics have anti-inflammatory effects⁷ as well that might be part of their efficacy beyond blocking dopamine D2 receptors.

Decrease free radicals. Microglia are activated by psychosis to release free radicals, also known as reactive oxygen species; these include nitric oxide, super­oxide, and peroxynitrate. All these spe­cies are destructive to brain tissue. Using an adjunctive strong antioxidant, such as N-acetyl cysteine,⁸ with an antipsychotic might help neutralize destructive effects of free radicals and protect the brain from tissue loss during a psychotic episode.

Avoid apoptosis inducers. Several sub­stances can initiate programmed cell death (apoptosis), which is triggered during psychosis (believed to be caused by increased dopamine and, possibly, glutamate, activity) and which leads to brain atrophy. Patients with schizophre­nia must be protected from these apop­tosis inducers:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

Apoptosis can be inhibited by main­taining high levels of neurotrophic factors. Atypical, but not typical, anti­psychotics increase levels of neuro­trophins, such as NGF and BDNF.⁴ In addition, the Bcl-2 family of proteins inhibits apoptosis,⁹ and drugs such as lithium and valproate can induce Bcl-2 and protect against apoptosis and neu­ronal loss.³

Restore white-matter integrity. Numerous studies using diffusion ten­sor imaging have revealed that myelin is reduced or lacks integrity in schizophre­nia. This results in loss of critical connec­tivity among brain regions, which might explain psychotic and cognitive symp­toms. One possible way to repair white matter, which becomes more damaged after multiple psychotic episodes, is to use drugs indicated to treat the demy­elinating disorder multiple sclerosis. Antagonists of LINGO-1, a negative regulator of axonal myelination, are a prominent possibility; a recent study reported altered signaling of LINGO-1 in schizophrenia.¹⁰

Decrease excessive glutamate. Because glutamate is neurotoxic and might contribute to brain-tissue loss during psychosis, it is important to reduce glutamate activity in schizophre­nia. Lamotrigine and valproate are both known to do that.¹¹ Several studies indi­cate that adjunctive lamotrigine might be helpful in schizophrenia.¹²

Inhibit caspase-3, also known as the “death cascade,” which is involved in brain-tissue loss. Eicosapentaenoic acid is an omega-3 fatty acid that inhibits caspase-3. Interestingly, omega-3 levels in patients with schizophrenia are signif­icantly lower than in healthy subjects.13 Lithium also can inhibit caspase-3.

Do these proposals sound radical?
Most of the recommendations I’ve made here are not employed in the clinical prac­tice of psychiatry. These ideas must be put to the test in controlled clinical trials.

The crux of my argument is that we need to think outside the “dopamine box” and focus on brain repair if we are to make progress in reversing, even pre­venting, neurodegeneration and clini­cal deterioration in this disabling brain syndrome. Just as cancer often is treated with rational polypharmacy, schizo­phrenia might need a similar approach. To vanquish schizophrenia—a goal that has eluded us—it is imperative to pur­sue radically novel and disruptive ther­apeutic strategies. The ideas I’ve listed here sound the call that the quest to repair the brain in schizophrenia must begin, and soon.

For the past 60 years, the standard of care has remained one-dimensional in this brain syndrome, even though the clini­cal and neurobiological complexities of schizophrenia are multidimensional. Dopamine D2 receptor antagonists, dis­covered serendipitously in the 1950s, have remained the mainstay of treat­ment, despite momentous insights about the neurodevelopmental and neurode­generative processes of schizophrenia.

Why do we ignore abundant evi­dence that the brain in schizophrenia needs extensive structural repair, not simply a reduction in the activity of a single neurotransmitter in the mesolim­bic dopamine tract? Perhaps the age-old dogmatic pessimism that neurodegen­eration cannot be reversed has inhibited the field from attempting to escape the dopamine box, so to speak, and from developing innovative, even radical, approaches to repair of the brain of per­sons with schizophrenia.

But radical thinking is justified when dealing with a cruel brain syndrome that disables young adults in the prime of life.

We should exploit neuroprotective tactics
Several neuroprotective approaches to preventing or reversing the degen­erative changes across brain regions in schizophrenia are now recognized. Indirect evidence exists for such inter­ventions in animal models, but the results of few controlled human studies have been published.

Here are my proposals for using neuroprotective tactics to address the unmet need to repair the brain of patients ravaged by neurotoxic psy­chotic relapses.

Promote 100% adherence to anti­psychotic therapy. The simplest tac­tic to protect the brain from atrophy in patients with schizophrenia is to use long-acting injectable antipsychotic agents immediately after the first psy­chotic episode. The risk of a psychotic relapse is far lower (7-fold lower, according to a study performed at the University of California, Los Angeles, that soon will be published) with an injectable medication than with oral medication in first-episode patients. Preventing psychotic episodes is, logi­cally, the most important neuroprotec­tive tactic.

Enhance neurogenesis. The brain has 2 neurogenic regions that produce pro­genitor cells (stem cells) that gradually mature and differentiate into neurons and glia. That is how the brain naturally replenishes itself throughout life. This adult neurogenesis process, carried out in the dentate gyrus of the hippocam­pus and in the subventricular zone, stops during psychosis but resumes when psychosis remits.

Second-generation antipsychotics (but not first-generation agents) stimulate neurogenesis in animals.¹ Haloperidol, in fact, does the opposite—suppressing neurogenesis and causing neuronal death via 15 different molecular mechanisms (see my editorial, “Haloperidol clearly is neurotoxic. Should it be banned?,” in the July 2013 issue).

Other psychotropics also induce neurogenesis, including selective serotonin reuptake inhibitors (SSRIs), which increase hippocampal neurogen­esis (atypical antipsychotics appear to increase neurogenesis in the subventric­ular zone).² SSRIs often have been used in schizophrenia patients for 2 common comorbid conditions: depression and anxiety. These agents can help regener­ate brain tissue, in addition to providing their approved therapeutic indications.

Lithium and valproate have been shown to be neuroprotective³ and to stimulate neurogenesis. Both are often used in schizoaffective disorder, bipolar type; they can exert a neuroprotective effect in addition to their clinical use­fulness. The combination of an SSRI or lithium with a second-generation anti­psychotic could be synergistic in tur­bocharging neurogenesis. This sounds like polypharmacy—but it is a rational approach that deserves to be put to the test.

Increase neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). When neurotrophin levels decline, the brain starts shrinking because of apoptosis. Psychosis lowers neurotrophins drasti­cally—by approximately 60%. Atypical antipsychotics have been reported to increase the level of neurotrophins; hal­operidol actually lowers those levels.⁴

Decrease inflammation. Psychosis has been shown to be associated with neuro-inflammation, as reflected in a surge of pro-inflammatory cytokines (released from activated microglia).⁵ A rise in interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and other pro-inflammatory markers has been extensively documented in many studies.

With that observed rise in mind, sev­eral controlled studies have shown that adding an anti-inflammatory agent (aspi­rin, a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or minocycline) to an antipsychotic can accentuate the therapeutic response, especially during a first episode of psychosis.⁶ Note also that second-generation antipsychotics have anti-inflammatory effects⁷ as well that might be part of their efficacy beyond blocking dopamine D2 receptors.

Decrease free radicals. Microglia are activated by psychosis to release free radicals, also known as reactive oxygen species; these include nitric oxide, super­oxide, and peroxynitrate. All these spe­cies are destructive to brain tissue. Using an adjunctive strong antioxidant, such as N-acetyl cysteine,⁸ with an antipsychotic might help neutralize destructive effects of free radicals and protect the brain from tissue loss during a psychotic episode.

Avoid apoptosis inducers. Several sub­stances can initiate programmed cell death (apoptosis), which is triggered during psychosis (believed to be caused by increased dopamine and, possibly, glutamate, activity) and which leads to brain atrophy. Patients with schizophre­nia must be protected from these apop­tosis inducers:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

Apoptosis can be inhibited by main­taining high levels of neurotrophic factors. Atypical, but not typical, anti­psychotics increase levels of neuro­trophins, such as NGF and BDNF.⁴ In addition, the Bcl-2 family of proteins inhibits apoptosis,⁹ and drugs such as lithium and valproate can induce Bcl-2 and protect against apoptosis and neu­ronal loss.³

Restore white-matter integrity. Numerous studies using diffusion ten­sor imaging have revealed that myelin is reduced or lacks integrity in schizophre­nia. This results in loss of critical connec­tivity among brain regions, which might explain psychotic and cognitive symp­toms. One possible way to repair white matter, which becomes more damaged after multiple psychotic episodes, is to use drugs indicated to treat the demy­elinating disorder multiple sclerosis. Antagonists of LINGO-1, a negative regulator of axonal myelination, are a prominent possibility; a recent study reported altered signaling of LINGO-1 in schizophrenia.¹⁰

Decrease excessive glutamate. Because glutamate is neurotoxic and might contribute to brain-tissue loss during psychosis, it is important to reduce glutamate activity in schizophre­nia. Lamotrigine and valproate are both known to do that.¹¹ Several studies indi­cate that adjunctive lamotrigine might be helpful in schizophrenia.¹²

Inhibit caspase-3, also known as the “death cascade,” which is involved in brain-tissue loss. Eicosapentaenoic acid is an omega-3 fatty acid that inhibits caspase-3. Interestingly, omega-3 levels in patients with schizophrenia are signif­icantly lower than in healthy subjects.13 Lithium also can inhibit caspase-3.

Do these proposals sound radical?
Most of the recommendations I’ve made here are not employed in the clinical prac­tice of psychiatry. These ideas must be put to the test in controlled clinical trials.

The crux of my argument is that we need to think outside the “dopamine box” and focus on brain repair if we are to make progress in reversing, even pre­venting, neurodegeneration and clini­cal deterioration in this disabling brain syndrome. Just as cancer often is treated with rational polypharmacy, schizo­phrenia might need a similar approach. To vanquish schizophrenia—a goal that has eluded us—it is imperative to pur­sue radically novel and disruptive ther­apeutic strategies. The ideas I’ve listed here sound the call that the quest to repair the brain in schizophrenia must begin, and soon.

In his most recent bestseller, Being Mortal, Dr. Atul Gawande has again raised social awareness of the inadequacies of our health care system in assisting patients with end-of-life decisions and care. In his treatise, he laments his own lack of training in medical school and residency regarding what he has emphasized should be a key component of any physician’s education.

To some degree, there has been a greater emphasis on palliative care training in our medical schools since Dr. Gawande graduated two decades or so ago. The subject of physician-patient communication, including those difficult discussions that should occur near the end of life, is now incorporated into most medical school curricula. Additionally, palliative care has become a respected and growing subspecialty within both medicine and surgery.* Despite these improvements, still far too many patients die while receiving futile end-of-life care in our nation’s intensive care units and hospital wards rather than in the comfort of their homes surrounded by loved ones. Although referrals have increased, too few patients are afforded the opportunity to utilize hospice care and, those that do, are often referred too late in the course of their terminal disease to obtain full benefit

Why are we not doing better? Two likely contributors include a physician mindset that only cure is success and death represents failure, and unrealistic expectations of patients as to what modern medicine can accomplish. A more fixable and probably more important factor is the failure of doctors to effectively communicate during these highly stressful circumstances. As emphasized by Gawande and from my own experience, the key to negotiating a sensible path in hopeless, end-of-life situations is frequent, reasonable, and realistic consultation with our patients.

Not only are the conversations usually difficult and demanding, but the choices of whether to pursue treatment or remove life-sustaining efforts are frequently not well-defined. While these challenging clinical scenarios are often painted as black and white in the lay press, any physician or surgeon who has cared for such patients realizes that there is a delicate and precarious balance between providing hope, administering appropriate aggressive treatment, and ensuring patient comfort. In a well-intentioned attempt to leave some remnant of hope, we physicians too frequently paint an unrealistic picture for our patients.

Advance patient directives have been promoted as one means for patients to avoid futile, uncomfortable, and unnecessary care during the last stage of their lives. Though I by no means wish to discourage these often useful legal documents, they should not be entered into naively. For example, aggressive life-sustaining care for a patient with extensive metastatic lung cancer is likely inappropriate. On the other hand, short-term ventilator assistance for an elderly unconscious person recovering from an automobile accident may result in many additional years of enjoyable and productive life. Patients need to understand that all grave clinical situations are not equal and that their advance directives should be flexible enough to cover a variety of circumstances.

It has been well established that most patients and families have selective hearing and understanding. Even when the details of a major operation with a greater likelihood of a negative rather than a positive outcome are carefully and clearly presented using lay language, the potential positive outcomes frequently push the more probable adverse consequences into hidden recesses of the brain. In my experience, the more desperate the situation, the more often it is that the possibility of an unsuccessful outcome will be masked or denied by patients or their family members. Even though in my practice I carefully explained the high probability of eventual recurrence when operating on patients with pancreatic cancer, many of them were surprised and some were even quite indignant when this disappointing consequence developed. In my opinion, the most effective means to avoid such misunderstandings is to always have the patient and/or family relate their comprehension of the just-completed conversation. It is then essential to re-emphasize the important details that they suppressed and pushed to the background from your initial explanation.

In these challenging end-of-life moments, what advice should we offer? One question that should almost never be asked of the patient or his/her representative is: “Would you like everything possible done?” Especially for a family member who may take on considerable guilt by answering in the negative, the response will nearly always be “yes” no matter how unlikely a successful outcome. Rather, I believe that recommending only reasonable options, including and possibly emphasizing the choice of comfort therapy alone despite the certainty of death, is our obligation. We should be cognizant of the fact that the decision made by the patient is often highly dependent on how the alternatives are presented by his/her doctor. After clearly presenting the therapeutic options and their likely consequences, it may be helpful to relate what you would do yourself for a loved one in the same circumstances.

As in many other aspects of our lives, a useful guidepost in these situations is the Golden Rule: “Do unto others as you would have done unto yourself.” Interestingly, most probably based on our intimate exposure to numerous unnecessarily complicated and uncomfortable deaths, there is evidence that we physicians choose to die differently than our patients. In a recent essay, Dr. Ken Murray presented data from the John Hopkins Precursors Study that suggested doctors are less likely than their patients to submit themselves to futile end-of-life care. (Murray K: Doctors really do die differently. Zocalopublicsquare.org; accessed March 29, 2015). The proof he presents is from a survey of graduates of Johns Hopkins School of Medicine between 1948 and 1964. It revealed that 65% of them had written their own advance directives in comparison to 20% for the public at large. In addition, only 10% of the graduates would opt for cardiopulmonary resuscitation if they were comatose, compared with 75% of the general population.

I suspect that most surgeons, desiring a dignified death for themselves, are not surprised by these statistics. Therefore, we owe it to our patients to be as compassionate and thoughtful in managing the last stage of their lives as we have traditionally been trained to do in earlier phases when cure was a realistic expectation.

Dr. Rikkers is Editor in Chief of ACS Surgery News.

*Recognizing the importance of end-of-life issues in a surgeon’s education, in 2012 ACS Surgery News initiated a series of articles on various aspects of palliative care.

In his most recent bestseller, Being Mortal, Dr. Atul Gawande has again raised social awareness of the inadequacies of our health care system in assisting patients with end-of-life decisions and care. In his treatise, he laments his own lack of training in medical school and residency regarding what he has emphasized should be a key component of any physician’s education.

To some degree, there has been a greater emphasis on palliative care training in our medical schools since Dr. Gawande graduated two decades or so ago. The subject of physician-patient communication, including those difficult discussions that should occur near the end of life, is now incorporated into most medical school curricula. Additionally, palliative care has become a respected and growing subspecialty within both medicine and surgery.* Despite these improvements, still far too many patients die while receiving futile end-of-life care in our nation’s intensive care units and hospital wards rather than in the comfort of their homes surrounded by loved ones. Although referrals have increased, too few patients are afforded the opportunity to utilize hospice care and, those that do, are often referred too late in the course of their terminal disease to obtain full benefit

Why are we not doing better? Two likely contributors include a physician mindset that only cure is success and death represents failure, and unrealistic expectations of patients as to what modern medicine can accomplish. A more fixable and probably more important factor is the failure of doctors to effectively communicate during these highly stressful circumstances. As emphasized by Gawande and from my own experience, the key to negotiating a sensible path in hopeless, end-of-life situations is frequent, reasonable, and realistic consultation with our patients.

Not only are the conversations usually difficult and demanding, but the choices of whether to pursue treatment or remove life-sustaining efforts are frequently not well-defined. While these challenging clinical scenarios are often painted as black and white in the lay press, any physician or surgeon who has cared for such patients realizes that there is a delicate and precarious balance between providing hope, administering appropriate aggressive treatment, and ensuring patient comfort. In a well-intentioned attempt to leave some remnant of hope, we physicians too frequently paint an unrealistic picture for our patients.

Advance patient directives have been promoted as one means for patients to avoid futile, uncomfortable, and unnecessary care during the last stage of their lives. Though I by no means wish to discourage these often useful legal documents, they should not be entered into naively. For example, aggressive life-sustaining care for a patient with extensive metastatic lung cancer is likely inappropriate. On the other hand, short-term ventilator assistance for an elderly unconscious person recovering from an automobile accident may result in many additional years of enjoyable and productive life. Patients need to understand that all grave clinical situations are not equal and that their advance directives should be flexible enough to cover a variety of circumstances.

It has been well established that most patients and families have selective hearing and understanding. Even when the details of a major operation with a greater likelihood of a negative rather than a positive outcome are carefully and clearly presented using lay language, the potential positive outcomes frequently push the more probable adverse consequences into hidden recesses of the brain. In my experience, the more desperate the situation, the more often it is that the possibility of an unsuccessful outcome will be masked or denied by patients or their family members. Even though in my practice I carefully explained the high probability of eventual recurrence when operating on patients with pancreatic cancer, many of them were surprised and some were even quite indignant when this disappointing consequence developed. In my opinion, the most effective means to avoid such misunderstandings is to always have the patient and/or family relate their comprehension of the just-completed conversation. It is then essential to re-emphasize the important details that they suppressed and pushed to the background from your initial explanation.

In these challenging end-of-life moments, what advice should we offer? One question that should almost never be asked of the patient or his/her representative is: “Would you like everything possible done?” Especially for a family member who may take on considerable guilt by answering in the negative, the response will nearly always be “yes” no matter how unlikely a successful outcome. Rather, I believe that recommending only reasonable options, including and possibly emphasizing the choice of comfort therapy alone despite the certainty of death, is our obligation. We should be cognizant of the fact that the decision made by the patient is often highly dependent on how the alternatives are presented by his/her doctor. After clearly presenting the therapeutic options and their likely consequences, it may be helpful to relate what you would do yourself for a loved one in the same circumstances.

As in many other aspects of our lives, a useful guidepost in these situations is the Golden Rule: “Do unto others as you would have done unto yourself.” Interestingly, most probably based on our intimate exposure to numerous unnecessarily complicated and uncomfortable deaths, there is evidence that we physicians choose to die differently than our patients. In a recent essay, Dr. Ken Murray presented data from the John Hopkins Precursors Study that suggested doctors are less likely than their patients to submit themselves to futile end-of-life care. (Murray K: Doctors really do die differently. Zocalopublicsquare.org; accessed March 29, 2015). The proof he presents is from a survey of graduates of Johns Hopkins School of Medicine between 1948 and 1964. It revealed that 65% of them had written their own advance directives in comparison to 20% for the public at large. In addition, only 10% of the graduates would opt for cardiopulmonary resuscitation if they were comatose, compared with 75% of the general population.

I suspect that most surgeons, desiring a dignified death for themselves, are not surprised by these statistics. Therefore, we owe it to our patients to be as compassionate and thoughtful in managing the last stage of their lives as we have traditionally been trained to do in earlier phases when cure was a realistic expectation.

Dr. Rikkers is Editor in Chief of ACS Surgery News.

*Recognizing the importance of end-of-life issues in a surgeon’s education, in 2012 ACS Surgery News initiated a series of articles on various aspects of palliative care.

In his most recent bestseller, Being Mortal, Dr. Atul Gawande has again raised social awareness of the inadequacies of our health care system in assisting patients with end-of-life decisions and care. In his treatise, he laments his own lack of training in medical school and residency regarding what he has emphasized should be a key component of any physician’s education.

To some degree, there has been a greater emphasis on palliative care training in our medical schools since Dr. Gawande graduated two decades or so ago. The subject of physician-patient communication, including those difficult discussions that should occur near the end of life, is now incorporated into most medical school curricula. Additionally, palliative care has become a respected and growing subspecialty within both medicine and surgery.* Despite these improvements, still far too many patients die while receiving futile end-of-life care in our nation’s intensive care units and hospital wards rather than in the comfort of their homes surrounded by loved ones. Although referrals have increased, too few patients are afforded the opportunity to utilize hospice care and, those that do, are often referred too late in the course of their terminal disease to obtain full benefit

Why are we not doing better? Two likely contributors include a physician mindset that only cure is success and death represents failure, and unrealistic expectations of patients as to what modern medicine can accomplish. A more fixable and probably more important factor is the failure of doctors to effectively communicate during these highly stressful circumstances. As emphasized by Gawande and from my own experience, the key to negotiating a sensible path in hopeless, end-of-life situations is frequent, reasonable, and realistic consultation with our patients.

Not only are the conversations usually difficult and demanding, but the choices of whether to pursue treatment or remove life-sustaining efforts are frequently not well-defined. While these challenging clinical scenarios are often painted as black and white in the lay press, any physician or surgeon who has cared for such patients realizes that there is a delicate and precarious balance between providing hope, administering appropriate aggressive treatment, and ensuring patient comfort. In a well-intentioned attempt to leave some remnant of hope, we physicians too frequently paint an unrealistic picture for our patients.

Advance patient directives have been promoted as one means for patients to avoid futile, uncomfortable, and unnecessary care during the last stage of their lives. Though I by no means wish to discourage these often useful legal documents, they should not be entered into naively. For example, aggressive life-sustaining care for a patient with extensive metastatic lung cancer is likely inappropriate. On the other hand, short-term ventilator assistance for an elderly unconscious person recovering from an automobile accident may result in many additional years of enjoyable and productive life. Patients need to understand that all grave clinical situations are not equal and that their advance directives should be flexible enough to cover a variety of circumstances.

It has been well established that most patients and families have selective hearing and understanding. Even when the details of a major operation with a greater likelihood of a negative rather than a positive outcome are carefully and clearly presented using lay language, the potential positive outcomes frequently push the more probable adverse consequences into hidden recesses of the brain. In my experience, the more desperate the situation, the more often it is that the possibility of an unsuccessful outcome will be masked or denied by patients or their family members. Even though in my practice I carefully explained the high probability of eventual recurrence when operating on patients with pancreatic cancer, many of them were surprised and some were even quite indignant when this disappointing consequence developed. In my opinion, the most effective means to avoid such misunderstandings is to always have the patient and/or family relate their comprehension of the just-completed conversation. It is then essential to re-emphasize the important details that they suppressed and pushed to the background from your initial explanation.

In these challenging end-of-life moments, what advice should we offer? One question that should almost never be asked of the patient or his/her representative is: “Would you like everything possible done?” Especially for a family member who may take on considerable guilt by answering in the negative, the response will nearly always be “yes” no matter how unlikely a successful outcome. Rather, I believe that recommending only reasonable options, including and possibly emphasizing the choice of comfort therapy alone despite the certainty of death, is our obligation. We should be cognizant of the fact that the decision made by the patient is often highly dependent on how the alternatives are presented by his/her doctor. After clearly presenting the therapeutic options and their likely consequences, it may be helpful to relate what you would do yourself for a loved one in the same circumstances.

As in many other aspects of our lives, a useful guidepost in these situations is the Golden Rule: “Do unto others as you would have done unto yourself.” Interestingly, most probably based on our intimate exposure to numerous unnecessarily complicated and uncomfortable deaths, there is evidence that we physicians choose to die differently than our patients. In a recent essay, Dr. Ken Murray presented data from the John Hopkins Precursors Study that suggested doctors are less likely than their patients to submit themselves to futile end-of-life care. (Murray K: Doctors really do die differently. Zocalopublicsquare.org; accessed March 29, 2015). The proof he presents is from a survey of graduates of Johns Hopkins School of Medicine between 1948 and 1964. It revealed that 65% of them had written their own advance directives in comparison to 20% for the public at large. In addition, only 10% of the graduates would opt for cardiopulmonary resuscitation if they were comatose, compared with 75% of the general population.

I suspect that most surgeons, desiring a dignified death for themselves, are not surprised by these statistics. Therefore, we owe it to our patients to be as compassionate and thoughtful in managing the last stage of their lives as we have traditionally been trained to do in earlier phases when cure was a realistic expectation.

Dr. Rikkers is Editor in Chief of ACS Surgery News.

*Recognizing the importance of end-of-life issues in a surgeon’s education, in 2012 ACS Surgery News initiated a series of articles on various aspects of palliative care.