Commentary

“SHOULD RISK-REDUCING GYNECOLOGIC SURGERY FOR BRCA MUTATION CARRIERS INCLUDE HYSTERECTOMY?”

ANDREW M. KAUNITZ, MD (WEB EXCLUSIVE, AUGUST 28, 2016)

Hysterectomy warranted?

I am wondering if Dr. Kaunitz really is recommending performing 270 hysterectomies to prevent one endometrial cancer? Is this justified given the risks from the hysterectomy itself, the economics of the disease, or any significant reductions in endometrial cancer mortality?

David O. Holtz, MD
Paoli, Pennsylvania

Dr. Kaunitz responds

I appreciate Dr. Holtz’s interest in my commentary on the role of hysterectomy as part of risk-reducing surgery in BRCA mutation carriers. Women who are mutation carriers are at increased risk for serous or serous-like endometrial cancers. Further, hysterectomy offers specific advantages for young mutation carriers for whom menopausal hormone therapy is often indicated after risk-reducing salpingo-oophorectomy. Accordingly, I would indeed encourage such women to consider hysterectomy as part of risk-reducing gynecologic surgery if such surgery can be accomplished via minimally invasive techniques.

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

“SHOULD RISK-REDUCING GYNECOLOGIC SURGERY FOR BRCA MUTATION CARRIERS INCLUDE HYSTERECTOMY?”

ANDREW M. KAUNITZ, MD (WEB EXCLUSIVE, AUGUST 28, 2016)

Hysterectomy warranted?

I am wondering if Dr. Kaunitz really is recommending performing 270 hysterectomies to prevent one endometrial cancer? Is this justified given the risks from the hysterectomy itself, the economics of the disease, or any significant reductions in endometrial cancer mortality?

David O. Holtz, MD
Paoli, Pennsylvania

Dr. Kaunitz responds

I appreciate Dr. Holtz’s interest in my commentary on the role of hysterectomy as part of risk-reducing surgery in BRCA mutation carriers. Women who are mutation carriers are at increased risk for serous or serous-like endometrial cancers. Further, hysterectomy offers specific advantages for young mutation carriers for whom menopausal hormone therapy is often indicated after risk-reducing salpingo-oophorectomy. Accordingly, I would indeed encourage such women to consider hysterectomy as part of risk-reducing gynecologic surgery if such surgery can be accomplished via minimally invasive techniques.

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

“SHOULD RISK-REDUCING GYNECOLOGIC SURGERY FOR BRCA MUTATION CARRIERS INCLUDE HYSTERECTOMY?”

ANDREW M. KAUNITZ, MD (WEB EXCLUSIVE, AUGUST 28, 2016)

Hysterectomy warranted?

I am wondering if Dr. Kaunitz really is recommending performing 270 hysterectomies to prevent one endometrial cancer? Is this justified given the risks from the hysterectomy itself, the economics of the disease, or any significant reductions in endometrial cancer mortality?

David O. Holtz, MD
Paoli, Pennsylvania

Dr. Kaunitz responds

I appreciate Dr. Holtz’s interest in my commentary on the role of hysterectomy as part of risk-reducing surgery in BRCA mutation carriers. Women who are mutation carriers are at increased risk for serous or serous-like endometrial cancers. Further, hysterectomy offers specific advantages for young mutation carriers for whom menopausal hormone therapy is often indicated after risk-reducing salpingo-oophorectomy. Accordingly, I would indeed encourage such women to consider hysterectomy as part of risk-reducing gynecologic surgery if such surgery can be accomplished via minimally invasive techniques.

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

Bone disease in patients with kidney disease is indeed a tricky interplay, as the article by Nyman et al (J Fam Pract. 2016;65:606-612) aptly states in its title.

The author made incorrect statements on page 607 regarding hyperphosphatemia and hypocalcemia and the escalation of fracture risk. (Editor’s Note: See erratum.)

In addition, on page 610, the article mentions that 1,25-(OH)₂ vitamin D may help prevent hypertension, myocardial infarction, and stroke in patients without chronic kidney disease. This is not supported by the literature and even the reference cited states that fact.

Roy N. Morcos, MD, FAAFP
Boardman, OH

 

 

Author’s response:

Thank you, Dr. Morcos, for your careful read of our article.

Despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.Regarding the discussion of 1,25-(OH)₂ vitamin D, we are in agreement. In fact, the last sentence of our paragraph reads: “There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.” We were simply calling attention to the fact that despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.

Karly Pippitt, MD,
on behalf of co-authors Heather Nyman, PharmD, BCPS;
Alisyn Hansen, PharmD, BCACP, CDE;
Karen Gunning, PharmD, BCPS, BCACP, FCCP
Salt Lake City, UT

Bone disease in patients with kidney disease is indeed a tricky interplay, as the article by Nyman et al (J Fam Pract. 2016;65:606-612) aptly states in its title.

The author made incorrect statements on page 607 regarding hyperphosphatemia and hypocalcemia and the escalation of fracture risk. (Editor’s Note: See erratum.)

In addition, on page 610, the article mentions that 1,25-(OH)₂ vitamin D may help prevent hypertension, myocardial infarction, and stroke in patients without chronic kidney disease. This is not supported by the literature and even the reference cited states that fact.

Roy N. Morcos, MD, FAAFP
Boardman, OH

 

 

Author’s response:

Thank you, Dr. Morcos, for your careful read of our article.

Despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.Regarding the discussion of 1,25-(OH)₂ vitamin D, we are in agreement. In fact, the last sentence of our paragraph reads: “There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.” We were simply calling attention to the fact that despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.

Karly Pippitt, MD,
on behalf of co-authors Heather Nyman, PharmD, BCPS;
Alisyn Hansen, PharmD, BCACP, CDE;
Karen Gunning, PharmD, BCPS, BCACP, FCCP
Salt Lake City, UT

Bone disease in patients with kidney disease is indeed a tricky interplay, as the article by Nyman et al (J Fam Pract. 2016;65:606-612) aptly states in its title.

The author made incorrect statements on page 607 regarding hyperphosphatemia and hypocalcemia and the escalation of fracture risk. (Editor’s Note: See erratum.)

In addition, on page 610, the article mentions that 1,25-(OH)₂ vitamin D may help prevent hypertension, myocardial infarction, and stroke in patients without chronic kidney disease. This is not supported by the literature and even the reference cited states that fact.

Roy N. Morcos, MD, FAAFP
Boardman, OH

 

 

Author’s response:

Thank you, Dr. Morcos, for your careful read of our article.

Despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.Regarding the discussion of 1,25-(OH)₂ vitamin D, we are in agreement. In fact, the last sentence of our paragraph reads: “There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.” We were simply calling attention to the fact that despite the lack of evidence, some providers are still prescribing native vitamin D for their patients with chronic kidney disease for reasons unrelated to parathyroid hormone suppression.

Karly Pippitt, MD,
on behalf of co-authors Heather Nyman, PharmD, BCPS;
Alisyn Hansen, PharmD, BCACP, CDE;
Karen Gunning, PharmD, BCPS, BCACP, FCCP
Salt Lake City, UT

Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.

Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.

Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.

Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.

Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.

Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

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

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

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

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

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