Mixed Topics

As many in the world react with sanctions imposed on Russia after its invasion of Ukraine, the oncology community has now stepped into the fray.

All the large cancer organizations have put out statements in support of Ukraine, but one group has gone further and cut its ties with Russia.

“The international cancer specialist network, OncoAlert, severed all cooperation with doctors in Russia as part of the Western sanctions,” the group announced on its Twitter page, which is decorated with a blue and yellow ribbon and declares that it “stands with Ukraine.”

“The OncoAlert Network is nonpolitical but we cannot stand idle and not take a stand against this aggression toward our Ukrainian friends & colleagues,” the group said. “The network will be pulling out of ALL collaborations & congresses in Russia.”

Not surprisingly, the post was inundated with a barrage of inflammatory and politically laced tweets from Russian and Chinese users. Many of them repeated the same phrase about “violating the Hippocratic oath and the Geneva convention,” used foul language, and slammed the United States for past military actions in other parts of the world.

A prominent Russian oncologist also responded, posting a video in which he discussed the situation more coherently and without mudslinging or scripted phrases. Andrey Kaprin, MD, PhD, is chief oncologist of the Russian Federation as well as director general of the Federal State Budgetary Institution, NMRCC, of the Ministry of Health of the Russian Federation. He says they continue to maintain relations with the largest and best known oncologic organizations. “We haven’t felt any deterioration in our relationship yet, and of course, we hope that this won’t happen.”

Dr. Kaprin said he believes OncoAlert will return to cooperation with Russia, and that “reason will prevail.”

“No one is protected from cancer, not even doctors, and that is why there should be no politics here,” he said.

Dr. Kaprin was speaking from Russia state-affiliated media, so it was not an independent commentary. Several of the Twitter responses to his video, primarily from non-Russians, were less than complimentary.

One user replied: “Cancer is rife in the Kremlin.”

Another post pointed out the hypocrisy of Russians being upset that OncoAlert was cutting ties with them. “What about sick Ukrainian kids, having to shelter in hospital basement, not having lifesaving surgeries because Russia decided to invade a democratic country?”

And another post was not buying the story that “reason will prevail,” in that the doctor’s talk seemed to contradict the reality of the situation. “I guess for every child #Russia murders they get cut off a little more from the civilized world?”
 

Cancer patients vulnerable

The war in Ukraine is an “unfolding humanitarian emergency,” said the World Health Organization, and it has called on top-level officials involved in the Russian invasion to ensure access for delivery of essential medical, surgical, and trauma supplies to help the Ukrainian people and refugees in neighboring countries. A shortage of oxygen, insulin, cancer therapies, and other essential supplies will continue to grow more dire in the weeks and months ahead, WHO officials predict.

One of the more heartbreaking reports described how pediatric cancer patients have been moved to hospital basements that are serving as temporary bomb shelters. Hospital staff continue to try to provide limited treatment when possible, even though essential supplies are dwindling. 

“These children suffer more because they need to stay alive to fight with the cancer – and this fight cannot wait,” Lesia Lysytsia, MD, a doctor at Okhmatdyt, the country’s largest children’s hospital in Kyiv, said in an NBC news report.

For some children, the only treatment available is a basic form of chemotherapy, and at the Kyiv Regional Oncology Center, the situation became so dire for children in need of blood transfusions that physicians began to transfuse blood from parent to child.

“Our patients, they will die,” Dr. Lysytsia said. “We will calculate how many people or soldiers have died in attacks, but we will never calculate how many patients weren’t diagnosed of disease in time, how many patients died because they didn’t receive treatment. It’s an epic amount of people.”
 

Response from oncology community

Many of the large American oncology groups have issued strong statements expressing their support for Ukraine and offering assistance.

The American Cancer Society has partnered with the American Society of Clinical Oncology and the Sidney Kimmel Cancer Center–Jefferson Health to support all Ukrainian cancer patients and their families. The groups are engaging a network of oncologists and oncology nurses to provide support through the ACS Clinician Volunteer Corps.

The ACS and ASCO are making free cancer resources available in English, Ukrainian, Polish, and Russian through their patient information websites (available here and here), with additional patient education resources planned. 

The ACS noted that there are more than 179,000 newly diagnosed patients with cancer among the Ukrainian people “suffering from Russia’s unprovoked aggression.”

“Disruptions to cancer treatment pose a grave risk to the survival of Ukrainian patients with cancer,” commented Karen Knudsen, PhD, CEO at the ACS.

ASCO also issued its own statement, declaring that it stands with “our Ukrainian members, the worldwide oncology community, and health care providers around the globe in condemning Russia’s unprovoked war on Ukraine.”

The society notes that it represents oncology professionals in Ukraine and neighboring countries including Poland, Romania, Moldova, Slovakia, and Hungary, which are now receiving thousands of refugees from the Russian invasion.

“We are hearing daily reports of cancer treatment interrupted by acts of war, including damage to medical facilities and shortages of critical supplies. Countless patients now need to find cancer care in new and unfamiliar surroundings with limited medical records and minimal resources,” the society commented.

The American Association for Cancer Research also issued a statement by President David A. Tuveson, MD, PhD, and CEO Margaret Foti, PhD, MD (hc). The organization has more than 50,000 members around the world, and they “stand in solidarity with the citizens of Ukraine during the Russian attack on their country.”

“This abhorrent war, which has been instigated by Russia’s leaders, is isolating and interrupting the lifesaving work of scientists and clinicians in Ukraine and Russia, threatening years of effective research collaborations and community building,” the AACR comments. “Limiting the exchange of innovative ideas, practices, and data across borders will significantly retard cancer research and have an adverse effect on public health.”

Perhaps the most subdued statement came from the European Society of Medical Oncology, in a brief release entitled: “Against Any War.” The society expressed profound sadness about the unfolding tragedy in Ukraine and the suffering of people. “We would like to confirm our solidarity and unconditioned support to all oncology professionals and cancer patients, with no geographical boundaries.”

ESMO also said that they were reviewing possibilities “to be of concrete help for our members and their patients, in collaboration with national and transnational oncology societies, as well as the International Cancer Foundation.”

A version of this article first appeared on Medscape.com.

As many in the world react with sanctions imposed on Russia after its invasion of Ukraine, the oncology community has now stepped into the fray.

All the large cancer organizations have put out statements in support of Ukraine, but one group has gone further and cut its ties with Russia.

“The international cancer specialist network, OncoAlert, severed all cooperation with doctors in Russia as part of the Western sanctions,” the group announced on its Twitter page, which is decorated with a blue and yellow ribbon and declares that it “stands with Ukraine.”

“The OncoAlert Network is nonpolitical but we cannot stand idle and not take a stand against this aggression toward our Ukrainian friends & colleagues,” the group said. “The network will be pulling out of ALL collaborations & congresses in Russia.”

Not surprisingly, the post was inundated with a barrage of inflammatory and politically laced tweets from Russian and Chinese users. Many of them repeated the same phrase about “violating the Hippocratic oath and the Geneva convention,” used foul language, and slammed the United States for past military actions in other parts of the world.

A prominent Russian oncologist also responded, posting a video in which he discussed the situation more coherently and without mudslinging or scripted phrases. Andrey Kaprin, MD, PhD, is chief oncologist of the Russian Federation as well as director general of the Federal State Budgetary Institution, NMRCC, of the Ministry of Health of the Russian Federation. He says they continue to maintain relations with the largest and best known oncologic organizations. “We haven’t felt any deterioration in our relationship yet, and of course, we hope that this won’t happen.”

Dr. Kaprin said he believes OncoAlert will return to cooperation with Russia, and that “reason will prevail.”

“No one is protected from cancer, not even doctors, and that is why there should be no politics here,” he said.

Dr. Kaprin was speaking from Russia state-affiliated media, so it was not an independent commentary. Several of the Twitter responses to his video, primarily from non-Russians, were less than complimentary.

One user replied: “Cancer is rife in the Kremlin.”

Another post pointed out the hypocrisy of Russians being upset that OncoAlert was cutting ties with them. “What about sick Ukrainian kids, having to shelter in hospital basement, not having lifesaving surgeries because Russia decided to invade a democratic country?”

And another post was not buying the story that “reason will prevail,” in that the doctor’s talk seemed to contradict the reality of the situation. “I guess for every child #Russia murders they get cut off a little more from the civilized world?”
 

Cancer patients vulnerable

The war in Ukraine is an “unfolding humanitarian emergency,” said the World Health Organization, and it has called on top-level officials involved in the Russian invasion to ensure access for delivery of essential medical, surgical, and trauma supplies to help the Ukrainian people and refugees in neighboring countries. A shortage of oxygen, insulin, cancer therapies, and other essential supplies will continue to grow more dire in the weeks and months ahead, WHO officials predict.

One of the more heartbreaking reports described how pediatric cancer patients have been moved to hospital basements that are serving as temporary bomb shelters. Hospital staff continue to try to provide limited treatment when possible, even though essential supplies are dwindling. 

“These children suffer more because they need to stay alive to fight with the cancer – and this fight cannot wait,” Lesia Lysytsia, MD, a doctor at Okhmatdyt, the country’s largest children’s hospital in Kyiv, said in an NBC news report.

For some children, the only treatment available is a basic form of chemotherapy, and at the Kyiv Regional Oncology Center, the situation became so dire for children in need of blood transfusions that physicians began to transfuse blood from parent to child.

“Our patients, they will die,” Dr. Lysytsia said. “We will calculate how many people or soldiers have died in attacks, but we will never calculate how many patients weren’t diagnosed of disease in time, how many patients died because they didn’t receive treatment. It’s an epic amount of people.”
 

Response from oncology community

Many of the large American oncology groups have issued strong statements expressing their support for Ukraine and offering assistance.

The American Cancer Society has partnered with the American Society of Clinical Oncology and the Sidney Kimmel Cancer Center–Jefferson Health to support all Ukrainian cancer patients and their families. The groups are engaging a network of oncologists and oncology nurses to provide support through the ACS Clinician Volunteer Corps.

The ACS and ASCO are making free cancer resources available in English, Ukrainian, Polish, and Russian through their patient information websites (available here and here), with additional patient education resources planned. 

The ACS noted that there are more than 179,000 newly diagnosed patients with cancer among the Ukrainian people “suffering from Russia’s unprovoked aggression.”

“Disruptions to cancer treatment pose a grave risk to the survival of Ukrainian patients with cancer,” commented Karen Knudsen, PhD, CEO at the ACS.

ASCO also issued its own statement, declaring that it stands with “our Ukrainian members, the worldwide oncology community, and health care providers around the globe in condemning Russia’s unprovoked war on Ukraine.”

The society notes that it represents oncology professionals in Ukraine and neighboring countries including Poland, Romania, Moldova, Slovakia, and Hungary, which are now receiving thousands of refugees from the Russian invasion.

“We are hearing daily reports of cancer treatment interrupted by acts of war, including damage to medical facilities and shortages of critical supplies. Countless patients now need to find cancer care in new and unfamiliar surroundings with limited medical records and minimal resources,” the society commented.

The American Association for Cancer Research also issued a statement by President David A. Tuveson, MD, PhD, and CEO Margaret Foti, PhD, MD (hc). The organization has more than 50,000 members around the world, and they “stand in solidarity with the citizens of Ukraine during the Russian attack on their country.”

“This abhorrent war, which has been instigated by Russia’s leaders, is isolating and interrupting the lifesaving work of scientists and clinicians in Ukraine and Russia, threatening years of effective research collaborations and community building,” the AACR comments. “Limiting the exchange of innovative ideas, practices, and data across borders will significantly retard cancer research and have an adverse effect on public health.”

Perhaps the most subdued statement came from the European Society of Medical Oncology, in a brief release entitled: “Against Any War.” The society expressed profound sadness about the unfolding tragedy in Ukraine and the suffering of people. “We would like to confirm our solidarity and unconditioned support to all oncology professionals and cancer patients, with no geographical boundaries.”

ESMO also said that they were reviewing possibilities “to be of concrete help for our members and their patients, in collaboration with national and transnational oncology societies, as well as the International Cancer Foundation.”

A version of this article first appeared on Medscape.com.

As many in the world react with sanctions imposed on Russia after its invasion of Ukraine, the oncology community has now stepped into the fray.

All the large cancer organizations have put out statements in support of Ukraine, but one group has gone further and cut its ties with Russia.

“The international cancer specialist network, OncoAlert, severed all cooperation with doctors in Russia as part of the Western sanctions,” the group announced on its Twitter page, which is decorated with a blue and yellow ribbon and declares that it “stands with Ukraine.”

“The OncoAlert Network is nonpolitical but we cannot stand idle and not take a stand against this aggression toward our Ukrainian friends & colleagues,” the group said. “The network will be pulling out of ALL collaborations & congresses in Russia.”

Not surprisingly, the post was inundated with a barrage of inflammatory and politically laced tweets from Russian and Chinese users. Many of them repeated the same phrase about “violating the Hippocratic oath and the Geneva convention,” used foul language, and slammed the United States for past military actions in other parts of the world.

A prominent Russian oncologist also responded, posting a video in which he discussed the situation more coherently and without mudslinging or scripted phrases. Andrey Kaprin, MD, PhD, is chief oncologist of the Russian Federation as well as director general of the Federal State Budgetary Institution, NMRCC, of the Ministry of Health of the Russian Federation. He says they continue to maintain relations with the largest and best known oncologic organizations. “We haven’t felt any deterioration in our relationship yet, and of course, we hope that this won’t happen.”

Dr. Kaprin said he believes OncoAlert will return to cooperation with Russia, and that “reason will prevail.”

“No one is protected from cancer, not even doctors, and that is why there should be no politics here,” he said.

Dr. Kaprin was speaking from Russia state-affiliated media, so it was not an independent commentary. Several of the Twitter responses to his video, primarily from non-Russians, were less than complimentary.

One user replied: “Cancer is rife in the Kremlin.”

Another post pointed out the hypocrisy of Russians being upset that OncoAlert was cutting ties with them. “What about sick Ukrainian kids, having to shelter in hospital basement, not having lifesaving surgeries because Russia decided to invade a democratic country?”

And another post was not buying the story that “reason will prevail,” in that the doctor’s talk seemed to contradict the reality of the situation. “I guess for every child #Russia murders they get cut off a little more from the civilized world?”
 

Cancer patients vulnerable

The war in Ukraine is an “unfolding humanitarian emergency,” said the World Health Organization, and it has called on top-level officials involved in the Russian invasion to ensure access for delivery of essential medical, surgical, and trauma supplies to help the Ukrainian people and refugees in neighboring countries. A shortage of oxygen, insulin, cancer therapies, and other essential supplies will continue to grow more dire in the weeks and months ahead, WHO officials predict.

One of the more heartbreaking reports described how pediatric cancer patients have been moved to hospital basements that are serving as temporary bomb shelters. Hospital staff continue to try to provide limited treatment when possible, even though essential supplies are dwindling. 

“These children suffer more because they need to stay alive to fight with the cancer – and this fight cannot wait,” Lesia Lysytsia, MD, a doctor at Okhmatdyt, the country’s largest children’s hospital in Kyiv, said in an NBC news report.

For some children, the only treatment available is a basic form of chemotherapy, and at the Kyiv Regional Oncology Center, the situation became so dire for children in need of blood transfusions that physicians began to transfuse blood from parent to child.

“Our patients, they will die,” Dr. Lysytsia said. “We will calculate how many people or soldiers have died in attacks, but we will never calculate how many patients weren’t diagnosed of disease in time, how many patients died because they didn’t receive treatment. It’s an epic amount of people.”
 

Response from oncology community

Many of the large American oncology groups have issued strong statements expressing their support for Ukraine and offering assistance.

The American Cancer Society has partnered with the American Society of Clinical Oncology and the Sidney Kimmel Cancer Center–Jefferson Health to support all Ukrainian cancer patients and their families. The groups are engaging a network of oncologists and oncology nurses to provide support through the ACS Clinician Volunteer Corps.

The ACS and ASCO are making free cancer resources available in English, Ukrainian, Polish, and Russian through their patient information websites (available here and here), with additional patient education resources planned. 

The ACS noted that there are more than 179,000 newly diagnosed patients with cancer among the Ukrainian people “suffering from Russia’s unprovoked aggression.”

“Disruptions to cancer treatment pose a grave risk to the survival of Ukrainian patients with cancer,” commented Karen Knudsen, PhD, CEO at the ACS.

ASCO also issued its own statement, declaring that it stands with “our Ukrainian members, the worldwide oncology community, and health care providers around the globe in condemning Russia’s unprovoked war on Ukraine.”

The society notes that it represents oncology professionals in Ukraine and neighboring countries including Poland, Romania, Moldova, Slovakia, and Hungary, which are now receiving thousands of refugees from the Russian invasion.

“We are hearing daily reports of cancer treatment interrupted by acts of war, including damage to medical facilities and shortages of critical supplies. Countless patients now need to find cancer care in new and unfamiliar surroundings with limited medical records and minimal resources,” the society commented.

The American Association for Cancer Research also issued a statement by President David A. Tuveson, MD, PhD, and CEO Margaret Foti, PhD, MD (hc). The organization has more than 50,000 members around the world, and they “stand in solidarity with the citizens of Ukraine during the Russian attack on their country.”

“This abhorrent war, which has been instigated by Russia’s leaders, is isolating and interrupting the lifesaving work of scientists and clinicians in Ukraine and Russia, threatening years of effective research collaborations and community building,” the AACR comments. “Limiting the exchange of innovative ideas, practices, and data across borders will significantly retard cancer research and have an adverse effect on public health.”

Perhaps the most subdued statement came from the European Society of Medical Oncology, in a brief release entitled: “Against Any War.” The society expressed profound sadness about the unfolding tragedy in Ukraine and the suffering of people. “We would like to confirm our solidarity and unconditioned support to all oncology professionals and cancer patients, with no geographical boundaries.”

ESMO also said that they were reviewing possibilities “to be of concrete help for our members and their patients, in collaboration with national and transnational oncology societies, as well as the International Cancer Foundation.”

A version of this article first appeared on Medscape.com.

What are the best tests for identification of a patient with chronic hepatitis B infection?

Continue to the answer...

Patients with chronic hepatitis B infection typically test positive for the hepatitis B surface antigen (HBsAg) and for IgG antibody to the hepatitis B core antigen (HBcAg). In addition, they also may test positive for the hepatitis B e antigen (HBeAg), and their viral load can be quantified by polymerase chain reaction (PCR) when significant antigenemia is present. The presence of the e antigen indicates a high rate of viral replication and a corresponding high rate of infectivity.

What are the best tests for identification of a patient with chronic hepatitis B infection?

Continue to the answer...

Patients with chronic hepatitis B infection typically test positive for the hepatitis B surface antigen (HBsAg) and for IgG antibody to the hepatitis B core antigen (HBcAg). In addition, they also may test positive for the hepatitis B e antigen (HBeAg), and their viral load can be quantified by polymerase chain reaction (PCR) when significant antigenemia is present. The presence of the e antigen indicates a high rate of viral replication and a corresponding high rate of infectivity.

What are the best tests for identification of a patient with chronic hepatitis B infection?

Continue to the answer...

Patients with chronic hepatitis B infection typically test positive for the hepatitis B surface antigen (HBsAg) and for IgG antibody to the hepatitis B core antigen (HBcAg). In addition, they also may test positive for the hepatitis B e antigen (HBeAg), and their viral load can be quantified by polymerase chain reaction (PCR) when significant antigenemia is present. The presence of the e antigen indicates a high rate of viral replication and a corresponding high rate of infectivity.

California-based emergency physician Simone Melissa Gold, MD, JD, founder of the antivaccine group America’s Frontline Doctors (AFD) and leading voice in the antivaccine movement, has pleaded guilty to one of five charges related to the Jan. 6 Capitol riot.

According to the plea deal, Dr. Gold pleaded guilty to charges that she “did unlawfully and knowingly enter and remain in a restricted building and grounds, that is, any posted, cordoned-off, or otherwise restricted area within the United States Capitol and its grounds, during a time when the vice president was in the building without lawful authority to do so.” As part of the agreement, additional charges against her – obstructing an official proceeding and intent to disrupt the orderly conduct of government business – will be dismissed. She also agreed to cooperate with investigators, including allowing them to review social media postings made during the time surrounding the event.

Shortly after she was indicted, Dr. Gold told The Washington Post that she did not see any violence and that the event was “peaceful.” However, according to news reports, Dr. Gold acknowledged in her plea deal that she and her codefendant, John Herbert Strand, witnessed the assault of a police officer while they were outside the building.

Dr. Gold, 56, based in Beverly Hills, Calif., founded AFD in 2019. The group notes its goal is to “amplify the voices of concerned physicians and patients nationwide to combat those who push political and economic agendas at the expense of science and quality health care solutions.” Mr. Strand is the organization’s communication’s director.

The group has been a leading proponent of the use of ivermectin as a “safe and effective treatment” for COVID-19, according to its website.

In 2021, Dr. Gold spoke at an event called The Stand, representing AFD, where she promised to tell “the truth” about COVID vaccines, including that it was actually giving people the virus, that COVID was renamed from the “Wuhan Virus” as part of a cover-up, and touted treatments, including hydroxycholoroquine and ivermectin.

Dr. Gold has been one of the leading voices in the anti-vaccine movement. She has more than 400,000 Twitter followers; her Twitter profile includes a pinned tweet saying: “We are living in Orwellian times.” In addition to spreading vaccine misinformation, Dr. Gold has promoted the use of unproven treatments such as hydroxychloroquine and ivermectin.

Calls and emails to AFD regarding a statement on Gold’s plea made by this news organization were not returned by press time.

In October, Representative James E. Clyburn (D-S.C.), chairman of the Select Subcommittee on the Coronavirus Crisis, launched an investigation into organizations, including AFD, that spread misinformation and facilitate access to disproven and potentially hazardous treatments for COVID-19. According to news reports, Rep. Clyburn called the AFD and other such groups “predatory actors.”

Hospitals where Dr. Gold previously worked, including Providence St. Joseph Medical Center in Santa Monica, Calif., and Cedars-Sinai in Los Angeles, have disassociated themselves from her. On July 29, 2020, Cedars-Sinai Medical Center, where Gold previously worked, issued a statement that said, in part, “Simone Gold, MD, has not worked with Cedars-Sinai Medical Center or any of its offices or affiliates since 2015. For 3 weeks in late 2015, Dr. Gold was employed on a per diem basis by Cedars-Sinai Medical Network, a component of Cedars-Sinai. She worked during this brief time in a network urgent care clinic. Dr. Gold is not authorized to represent or speak about any information on behalf of Cedars-Sinai.”

Dr. Gold’s medical license in the state of California is current and she has no pending hearings before the state medical board, according to its website. On her own website, Dr. Gold says she “voluntarily refused” to renew her board certification last year, “due to the unethical behavior of the medical boards.”

Dr. Gold is also a licensed attorney, having earned her law degree in health policy analysis at Stanford (Calif.) Law School.

Dr. Gold faces 6 months in prison. Sentencing is scheduled for June 16.

A version of this article first appeared on Medscape.com.

California-based emergency physician Simone Melissa Gold, MD, JD, founder of the antivaccine group America’s Frontline Doctors (AFD) and leading voice in the antivaccine movement, has pleaded guilty to one of five charges related to the Jan. 6 Capitol riot.

According to the plea deal, Dr. Gold pleaded guilty to charges that she “did unlawfully and knowingly enter and remain in a restricted building and grounds, that is, any posted, cordoned-off, or otherwise restricted area within the United States Capitol and its grounds, during a time when the vice president was in the building without lawful authority to do so.” As part of the agreement, additional charges against her – obstructing an official proceeding and intent to disrupt the orderly conduct of government business – will be dismissed. She also agreed to cooperate with investigators, including allowing them to review social media postings made during the time surrounding the event.

Shortly after she was indicted, Dr. Gold told The Washington Post that she did not see any violence and that the event was “peaceful.” However, according to news reports, Dr. Gold acknowledged in her plea deal that she and her codefendant, John Herbert Strand, witnessed the assault of a police officer while they were outside the building.

Dr. Gold, 56, based in Beverly Hills, Calif., founded AFD in 2019. The group notes its goal is to “amplify the voices of concerned physicians and patients nationwide to combat those who push political and economic agendas at the expense of science and quality health care solutions.” Mr. Strand is the organization’s communication’s director.

The group has been a leading proponent of the use of ivermectin as a “safe and effective treatment” for COVID-19, according to its website.

In 2021, Dr. Gold spoke at an event called The Stand, representing AFD, where she promised to tell “the truth” about COVID vaccines, including that it was actually giving people the virus, that COVID was renamed from the “Wuhan Virus” as part of a cover-up, and touted treatments, including hydroxycholoroquine and ivermectin.

Dr. Gold has been one of the leading voices in the anti-vaccine movement. She has more than 400,000 Twitter followers; her Twitter profile includes a pinned tweet saying: “We are living in Orwellian times.” In addition to spreading vaccine misinformation, Dr. Gold has promoted the use of unproven treatments such as hydroxychloroquine and ivermectin.

Calls and emails to AFD regarding a statement on Gold’s plea made by this news organization were not returned by press time.

In October, Representative James E. Clyburn (D-S.C.), chairman of the Select Subcommittee on the Coronavirus Crisis, launched an investigation into organizations, including AFD, that spread misinformation and facilitate access to disproven and potentially hazardous treatments for COVID-19. According to news reports, Rep. Clyburn called the AFD and other such groups “predatory actors.”

Hospitals where Dr. Gold previously worked, including Providence St. Joseph Medical Center in Santa Monica, Calif., and Cedars-Sinai in Los Angeles, have disassociated themselves from her. On July 29, 2020, Cedars-Sinai Medical Center, where Gold previously worked, issued a statement that said, in part, “Simone Gold, MD, has not worked with Cedars-Sinai Medical Center or any of its offices or affiliates since 2015. For 3 weeks in late 2015, Dr. Gold was employed on a per diem basis by Cedars-Sinai Medical Network, a component of Cedars-Sinai. She worked during this brief time in a network urgent care clinic. Dr. Gold is not authorized to represent or speak about any information on behalf of Cedars-Sinai.”

Dr. Gold’s medical license in the state of California is current and she has no pending hearings before the state medical board, according to its website. On her own website, Dr. Gold says she “voluntarily refused” to renew her board certification last year, “due to the unethical behavior of the medical boards.”

Dr. Gold is also a licensed attorney, having earned her law degree in health policy analysis at Stanford (Calif.) Law School.

Dr. Gold faces 6 months in prison. Sentencing is scheduled for June 16.

A version of this article first appeared on Medscape.com.

California-based emergency physician Simone Melissa Gold, MD, JD, founder of the antivaccine group America’s Frontline Doctors (AFD) and leading voice in the antivaccine movement, has pleaded guilty to one of five charges related to the Jan. 6 Capitol riot.

According to the plea deal, Dr. Gold pleaded guilty to charges that she “did unlawfully and knowingly enter and remain in a restricted building and grounds, that is, any posted, cordoned-off, or otherwise restricted area within the United States Capitol and its grounds, during a time when the vice president was in the building without lawful authority to do so.” As part of the agreement, additional charges against her – obstructing an official proceeding and intent to disrupt the orderly conduct of government business – will be dismissed. She also agreed to cooperate with investigators, including allowing them to review social media postings made during the time surrounding the event.

Shortly after she was indicted, Dr. Gold told The Washington Post that she did not see any violence and that the event was “peaceful.” However, according to news reports, Dr. Gold acknowledged in her plea deal that she and her codefendant, John Herbert Strand, witnessed the assault of a police officer while they were outside the building.

Dr. Gold, 56, based in Beverly Hills, Calif., founded AFD in 2019. The group notes its goal is to “amplify the voices of concerned physicians and patients nationwide to combat those who push political and economic agendas at the expense of science and quality health care solutions.” Mr. Strand is the organization’s communication’s director.

The group has been a leading proponent of the use of ivermectin as a “safe and effective treatment” for COVID-19, according to its website.

In 2021, Dr. Gold spoke at an event called The Stand, representing AFD, where she promised to tell “the truth” about COVID vaccines, including that it was actually giving people the virus, that COVID was renamed from the “Wuhan Virus” as part of a cover-up, and touted treatments, including hydroxycholoroquine and ivermectin.

Dr. Gold has been one of the leading voices in the anti-vaccine movement. She has more than 400,000 Twitter followers; her Twitter profile includes a pinned tweet saying: “We are living in Orwellian times.” In addition to spreading vaccine misinformation, Dr. Gold has promoted the use of unproven treatments such as hydroxychloroquine and ivermectin.

Calls and emails to AFD regarding a statement on Gold’s plea made by this news organization were not returned by press time.

In October, Representative James E. Clyburn (D-S.C.), chairman of the Select Subcommittee on the Coronavirus Crisis, launched an investigation into organizations, including AFD, that spread misinformation and facilitate access to disproven and potentially hazardous treatments for COVID-19. According to news reports, Rep. Clyburn called the AFD and other such groups “predatory actors.”

Hospitals where Dr. Gold previously worked, including Providence St. Joseph Medical Center in Santa Monica, Calif., and Cedars-Sinai in Los Angeles, have disassociated themselves from her. On July 29, 2020, Cedars-Sinai Medical Center, where Gold previously worked, issued a statement that said, in part, “Simone Gold, MD, has not worked with Cedars-Sinai Medical Center or any of its offices or affiliates since 2015. For 3 weeks in late 2015, Dr. Gold was employed on a per diem basis by Cedars-Sinai Medical Network, a component of Cedars-Sinai. She worked during this brief time in a network urgent care clinic. Dr. Gold is not authorized to represent or speak about any information on behalf of Cedars-Sinai.”

Dr. Gold’s medical license in the state of California is current and she has no pending hearings before the state medical board, according to its website. On her own website, Dr. Gold says she “voluntarily refused” to renew her board certification last year, “due to the unethical behavior of the medical boards.”

Dr. Gold is also a licensed attorney, having earned her law degree in health policy analysis at Stanford (Calif.) Law School.

Dr. Gold faces 6 months in prison. Sentencing is scheduled for June 16.

A version of this article first appeared on Medscape.com.

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

A version of this article first appeared on Medscape.com.

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

A version of this article first appeared on Medscape.com.

A former pain medicine physician received a sentence of 20 years in prison for selling opioids and writing prescriptions for patients who were abusing or diverting the medications.

Patrick Titus, 58, operated Lighthouse Internal Medicine in Milford, Delaware, from 2005-2014.

Federal prosecutors said Mr. Titus unlawfully distributed or dispensed opioids including fentanyl, morphine, methadone, OxyContin, and oxycodone outside the scope of practice and often prescribed them in combination with each other or in other dangerous combinations. Mr. Titus distributed over 1 million pills, said the government.

In a 2018 indictment, the government said that Mr. Titus would, “at the first and nearly every follow-up visit” prescribe opioids in high dosages, often without conducting an exam or reviewing any urine test results. He would also write prescriptions for opioids without getting patients’s prior medical records or reviewing test results and rarely referred patients to alternative pain treatments such as physical therapy, psychotherapy, or massage.

According to the indictment, he ignored “red flags,” including that patients would come from long distances, sometimes from out of state, and would pay cash, despite having Medicaid coverage.

“Today’s sentencing makes clear that medical professionals who recklessly prescribe opioids and endanger the safety and health of patients will be held accountable,” said Anne Milgram, a Drug Enforcement Administration administrator.

“This sentence is a reminder that the Department of Justice will hold accountable those doctors who are illegitimately prescribing opioids and fueling the country’s opioid crisis,” said Assistant Attorney General Kenneth A. Polite Jr., of the Justice Department’s Criminal Division, in the same statement. “Doctors who commit these unlawful acts exploit their roles as stewards of their patients’s care for their own profit,” he added.

The sentence follows Mr. Titus’s 2-week jury trial in 2021, when he was convicted of 13 counts of unlawful distribution and dispensing of controlled substances and one count of maintaining his practice primarily as a location to sell drugs. Mr. Titus faced a maximum of 20 years per count.

At the time of his conviction, Mr. Titus’s attorney said he planned to appeal, according to Delaware Online.

Delaware suspended Mr. Titus’s registration to prescribe controlled substances for 1 year in 2011. At the time, the state said it had determined that his continued prescribing “poses [an] imminent danger to the public health or safety.”

The state found that from January to November 2011, Mr. Titus issued 3,941 prescriptions for almost 750,000 pills for 17 different controlled substances, all sent to a single pharmacy.

The state also alleged that he wrote prescriptions for controlled substances to patients with felony convictions for drug trafficking and to at least one patient who his staff told him was selling the opioid that Mr. Titus had prescribed. It later determined that Mr. Titus continued prescribing even after it had suspended his DEA registration.

According to a 2014 consent agreement, the state subsequently ordered another 1-year suspension of his DEA registration, to be followed by a 3-year probation period.

Meanwhile, the same year, the state Board of Medical Licensure put Mr. Titus’s medical license on probation for 2 years and ordered him to complete 15 continuing medical education credits in medical recordkeeping, ethics, how to detect diversion and abuse, and in some other areas, and to pay a $7,500 fine.

In 2016, the medical board revoked Mr. Titus’s license, after finding that he continued to prescribe pain medications to patients he did not screen or monitor and for a multitude of other infractions.

A version of this article first appeared on Medscape.com.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

A version of this article first appeared on Medscape.com.

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

A version of this article first appeared on Medscape.com.

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

A version of this article first appeared on Medscape.com.

TikTok users seeking deep tans are employing a questionable method: spraying self-tanning products up their noses, and then laying out in the sun or in a tanning bed.

Although nasal spray tanning is being described as a new “viral” trend, it seems to have gotten its start as early as the spring of 2021. The tanning method appears to be especially popular in the United Kingdom, where self-tanning product brands have TikTok videos promoting nasal sprays.

The rising concerns of this and other viral TikTok trends has now prompted a bipartisan group of seven state attorneys general to launch an investigation.

“As children and teens already grapple with issues of anxiety, social pressure, and depression, we cannot allow social media to further harm their physical health and mental wellbeing,” Massachusetts Attorney General Maura Healey, a Democrat, said in a statement. “State attorneys general have an imperative to protect young people and seek more information about how companies like TikTok are influencing their daily lives.”

Ms. Healey, along with colleagues from California, Florida, Kentucky, Nebraska, New Jersey, Tennessee, and Vermont, will whether Chinese-based TikTok violates state consumer protection laws.

The trend of people shooting spray tan up their nose is just the latest in a long line of so-called TikTok challenges that have caused controversy, and often, injury.

In a February TikTok, put out by the British company So Tanned (@_sotanned), a young woman appears with text stating that she uses nasal spray “morning and night” and then adds self-tanning oral drops a half hour before getting into a tanning bed.

But, dermatologist Lily Talakoub, MD, of McLean, Va., posted a TikTok with the bold warning “DO NOT USE NASAL TANNING SPRAY!” In the video, the white coat–clad Dr. Talakoub is in the foreground of the TikTok made by @Sashawoodx.

“Don’t try this at home,” said Dr. Talakoub.

“Don’t try this even if you think it can make you tanner. It can cause nausea, vomiting, very bad side effects,” she said, adding “this can be very dangerous to your health.”

It’s also worth mentioning that self-tanning products are not approved by the Food and Drug Administration for inhalation.

Still, another U.K. company, 2btanned, posted a TikTok showing a user spraying the product up his nose and, in the comments, @2btanned suggested that the spray should be used at least a week or two before sun exposure “in order to get full effects.”

@Sashawoodx tells her viewers: “Don’t walk ... RUN for these products,” as she shows herself in several different outfits, squirting 2btanned spray up her nose. As of March 2, the TikTok video had been viewed over 212,000 times.

TikTokker @giannaarose, who has 125,000 followers, said in a video that she uses two to three sprays up the nose before stepping into the tanning bed. A commenter said, “this is scary but where do I buy it”.

The main ingredient in self-tanning products is dihydroxyacetone, or DHA. DHA, which is FDA-approved for use on skin, causes a chemical reaction when heat is applied, and a pigment is deposited on the skin.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said, given that self-tanning products were never meant to be inhaled and that nasal sprays of any kind must be approved by the FDA, a company promoting the products is engaged in a dangerous game.

“People could go to jail over this,” said Dr. Friedman. What’s more, the products are unlikely to produce a tan.

“Because of the way self-tanners work, it would make no sense,” said Dr. Friedman.

“It’s purely a camouflage,” he said, adding that it does not produce melanin. Self-tanners were never intended to be inhaled, “so who knows what those ingredients would do to a different anatomical site like the inner passages of the nose.”

At a minimum, spraying into the nose could at cause irritation. But it could also potentially lead to acute or long-term damage, he said.

Some other spray ingredients, such as tyrosine and tyrosinase, are involved in producing melanin, but they only act within skin cells. If sprayed into the nose, the ingredients might produce melanin inside the nose, but not on the skin.

“This is not going to work,” said Dr. Friedman. “If anything, it could be dangerous.”

He added that there’s no such thing as a safe tan, and that self-tanning products offer no protection from dangerous ultraviolet rays. The nasal sprays are “quick fixes” that are not going to work.

“At the end of the day, just don’t inhale,” Dr. Friedman said.

A version of this article first appeared on WebMD.com.

TikTok users seeking deep tans are employing a questionable method: spraying self-tanning products up their noses, and then laying out in the sun or in a tanning bed.

Although nasal spray tanning is being described as a new “viral” trend, it seems to have gotten its start as early as the spring of 2021. The tanning method appears to be especially popular in the United Kingdom, where self-tanning product brands have TikTok videos promoting nasal sprays.

The rising concerns of this and other viral TikTok trends has now prompted a bipartisan group of seven state attorneys general to launch an investigation.

“As children and teens already grapple with issues of anxiety, social pressure, and depression, we cannot allow social media to further harm their physical health and mental wellbeing,” Massachusetts Attorney General Maura Healey, a Democrat, said in a statement. “State attorneys general have an imperative to protect young people and seek more information about how companies like TikTok are influencing their daily lives.”

Ms. Healey, along with colleagues from California, Florida, Kentucky, Nebraska, New Jersey, Tennessee, and Vermont, will whether Chinese-based TikTok violates state consumer protection laws.

The trend of people shooting spray tan up their nose is just the latest in a long line of so-called TikTok challenges that have caused controversy, and often, injury.

In a February TikTok, put out by the British company So Tanned (@_sotanned), a young woman appears with text stating that she uses nasal spray “morning and night” and then adds self-tanning oral drops a half hour before getting into a tanning bed.

But, dermatologist Lily Talakoub, MD, of McLean, Va., posted a TikTok with the bold warning “DO NOT USE NASAL TANNING SPRAY!” In the video, the white coat–clad Dr. Talakoub is in the foreground of the TikTok made by @Sashawoodx.

“Don’t try this at home,” said Dr. Talakoub.

“Don’t try this even if you think it can make you tanner. It can cause nausea, vomiting, very bad side effects,” she said, adding “this can be very dangerous to your health.”

It’s also worth mentioning that self-tanning products are not approved by the Food and Drug Administration for inhalation.

Still, another U.K. company, 2btanned, posted a TikTok showing a user spraying the product up his nose and, in the comments, @2btanned suggested that the spray should be used at least a week or two before sun exposure “in order to get full effects.”

@Sashawoodx tells her viewers: “Don’t walk ... RUN for these products,” as she shows herself in several different outfits, squirting 2btanned spray up her nose. As of March 2, the TikTok video had been viewed over 212,000 times.

TikTokker @giannaarose, who has 125,000 followers, said in a video that she uses two to three sprays up the nose before stepping into the tanning bed. A commenter said, “this is scary but where do I buy it”.

The main ingredient in self-tanning products is dihydroxyacetone, or DHA. DHA, which is FDA-approved for use on skin, causes a chemical reaction when heat is applied, and a pigment is deposited on the skin.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said, given that self-tanning products were never meant to be inhaled and that nasal sprays of any kind must be approved by the FDA, a company promoting the products is engaged in a dangerous game.

“People could go to jail over this,” said Dr. Friedman. What’s more, the products are unlikely to produce a tan.

“Because of the way self-tanners work, it would make no sense,” said Dr. Friedman.

“It’s purely a camouflage,” he said, adding that it does not produce melanin. Self-tanners were never intended to be inhaled, “so who knows what those ingredients would do to a different anatomical site like the inner passages of the nose.”

At a minimum, spraying into the nose could at cause irritation. But it could also potentially lead to acute or long-term damage, he said.

Some other spray ingredients, such as tyrosine and tyrosinase, are involved in producing melanin, but they only act within skin cells. If sprayed into the nose, the ingredients might produce melanin inside the nose, but not on the skin.

“This is not going to work,” said Dr. Friedman. “If anything, it could be dangerous.”

He added that there’s no such thing as a safe tan, and that self-tanning products offer no protection from dangerous ultraviolet rays. The nasal sprays are “quick fixes” that are not going to work.

“At the end of the day, just don’t inhale,” Dr. Friedman said.

A version of this article first appeared on WebMD.com.

TikTok users seeking deep tans are employing a questionable method: spraying self-tanning products up their noses, and then laying out in the sun or in a tanning bed.

Although nasal spray tanning is being described as a new “viral” trend, it seems to have gotten its start as early as the spring of 2021. The tanning method appears to be especially popular in the United Kingdom, where self-tanning product brands have TikTok videos promoting nasal sprays.

The rising concerns of this and other viral TikTok trends has now prompted a bipartisan group of seven state attorneys general to launch an investigation.

“As children and teens already grapple with issues of anxiety, social pressure, and depression, we cannot allow social media to further harm their physical health and mental wellbeing,” Massachusetts Attorney General Maura Healey, a Democrat, said in a statement. “State attorneys general have an imperative to protect young people and seek more information about how companies like TikTok are influencing their daily lives.”

Ms. Healey, along with colleagues from California, Florida, Kentucky, Nebraska, New Jersey, Tennessee, and Vermont, will whether Chinese-based TikTok violates state consumer protection laws.

The trend of people shooting spray tan up their nose is just the latest in a long line of so-called TikTok challenges that have caused controversy, and often, injury.

In a February TikTok, put out by the British company So Tanned (@_sotanned), a young woman appears with text stating that she uses nasal spray “morning and night” and then adds self-tanning oral drops a half hour before getting into a tanning bed.

But, dermatologist Lily Talakoub, MD, of McLean, Va., posted a TikTok with the bold warning “DO NOT USE NASAL TANNING SPRAY!” In the video, the white coat–clad Dr. Talakoub is in the foreground of the TikTok made by @Sashawoodx.

“Don’t try this at home,” said Dr. Talakoub.

“Don’t try this even if you think it can make you tanner. It can cause nausea, vomiting, very bad side effects,” she said, adding “this can be very dangerous to your health.”

It’s also worth mentioning that self-tanning products are not approved by the Food and Drug Administration for inhalation.

Still, another U.K. company, 2btanned, posted a TikTok showing a user spraying the product up his nose and, in the comments, @2btanned suggested that the spray should be used at least a week or two before sun exposure “in order to get full effects.”

@Sashawoodx tells her viewers: “Don’t walk ... RUN for these products,” as she shows herself in several different outfits, squirting 2btanned spray up her nose. As of March 2, the TikTok video had been viewed over 212,000 times.

TikTokker @giannaarose, who has 125,000 followers, said in a video that she uses two to three sprays up the nose before stepping into the tanning bed. A commenter said, “this is scary but where do I buy it”.

The main ingredient in self-tanning products is dihydroxyacetone, or DHA. DHA, which is FDA-approved for use on skin, causes a chemical reaction when heat is applied, and a pigment is deposited on the skin.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said, given that self-tanning products were never meant to be inhaled and that nasal sprays of any kind must be approved by the FDA, a company promoting the products is engaged in a dangerous game.

“People could go to jail over this,” said Dr. Friedman. What’s more, the products are unlikely to produce a tan.

“Because of the way self-tanners work, it would make no sense,” said Dr. Friedman.

“It’s purely a camouflage,” he said, adding that it does not produce melanin. Self-tanners were never intended to be inhaled, “so who knows what those ingredients would do to a different anatomical site like the inner passages of the nose.”

At a minimum, spraying into the nose could at cause irritation. But it could also potentially lead to acute or long-term damage, he said.

Some other spray ingredients, such as tyrosine and tyrosinase, are involved in producing melanin, but they only act within skin cells. If sprayed into the nose, the ingredients might produce melanin inside the nose, but not on the skin.

“This is not going to work,” said Dr. Friedman. “If anything, it could be dangerous.”

He added that there’s no such thing as a safe tan, and that self-tanning products offer no protection from dangerous ultraviolet rays. The nasal sprays are “quick fixes” that are not going to work.

“At the end of the day, just don’t inhale,” Dr. Friedman said.

A version of this article first appeared on WebMD.com.

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

A version of this article first appeared on Medscape.com.

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

A version of this article first appeared on Medscape.com.

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

A version of this article first appeared on Medscape.com.

As one of 4 statutory missions, the US Department of Veterans Affairs (VA) educates and trains health professionals to enhance the quality of and timely access to care provided to veterans within the Veterans Health Administration (VHA). To achieve its mission to educate, the VA has conducted health professions education and training in partnership with affiliated US academic institutions for the past 76 years in accordance with the landmark 1946 Policy Memorandum No. 2.^1,2

Despite its long-term success affiliating with medical schools, VA has continued to be challenged by physician staff shortages with wide variability in the number and specialty of available health care professionals across facilities.^3,4 A 2020 VA Office of Inspector General report on VHA occupational staffing shortages concluded that numerous physician specialties were difficult to recruit due to a lack of qualified applicants, noncompetitive salary, and less desirable geographic locations.³

Federal health professions scholarship programs and loan repayment programs have long been used to address physician shortages.⁴ Focusing on physician shortages in underserved areas in the US, the Emergency Health Personnel Act of 1970 and its subsequent amendments paved the way for various federal medical school scholarship and loan repayment programs.⁵ Similarly, physician shortages in the armed forces were mitigated through the Uniformed Services Health Professions Revitalization Act of 1972 (USHPRA).^6,7

In 2018, Congress passed the VA MISSION (Maintaining Internal Systems and Strengthening Integrated Outside Networks) Act, which included sections designed to alleviate physician shortages in the VHA.⁸ These sections authorized scholarships similar to those offered by the US Department of Defense (DoD) and loan repayment programs. Section 301 created the Health Professions Scholarship Program (HPSP), which offers scholarships for physicians and dentists. Section 302 increased the maximum debt reduction through the Education Debt Reduction Program (EDRP). Section 303 authorizes the Specialty Education Loan Repayment Program (SELRP), which provides for repayment of educational loans for physicians in specialties deemed necessary for VA. Finally, Section 304 created the Veterans Healing Veterans (VHV), a pilot scholarship specifically for veteran medical students.
 

Program Characteristics

Health Professions Scholarship

The VA HPSP is a program for physicians and dentists that extends from 2020 to 2033. The HPSP funds the costs of tuition, fees, and provides a stipend with a service obligation of 18 months for each year of support. The program is authorized for 10 years and must provide a minimum of 50 scholarships annually for physicians or dentists based on VHA needs. Applications are screened based on criteria that include a commitment to rural or underserved populations, veteran status, grade point average, essays, and letters of recommendation. Although the minimum required number of scholarships annually is 50, VA anticipates providing 1000 scholarships over 10 years with an aim to significantly increase the number physicians at VHA facilities (Table 1).

Veterans Healing Veterans

Implemented in 2020, the VHV was a 1-year pilot program. It offered scholarships to 2 veterans attending medical school at each of the 5 Teague-Cranston and the 4 Historically Black College and University (HBCU) medical schools (Table 2). The intent of the program was to determine the feasibility of increasing the pool of veteran physicians at VHA. Eligible applicants were notified of the scholarship opportunity through the American Medical College Application Service or through the medical school. Applicants must have separated from military service within the preceding 10 years of being admitted to medical school. In exchange for full tuition, fees, a monthly stipend, and rotation travel costs, the recipients accepted a 4-year clinical service obligation at VA facilities after completing their residency training.

Specialty Education Loan Repayment

The SELRP is a loan repayment program available to recently graduated physicians. Applicants must have graduated from an accredited medical or osteopathic school, matched to an accredited residency program and be ≥ 2 years from completion of residency. The specialties qualifying for SELRP are determined through an analysis of succession planning by the VA Office of Workforce Management and Consulting and change based on VA physician workforce needs. The SELRP provides loan repayment in the amount of $40,000 per year for up to 4 years, with a service obligation of 1 year for each $40,000 of support. In April 2021, VA began accepting applications from the eligible specialties of family medicine, internal medicine, gastroenterology, psychiatry, emergency medicine, and geriatrics.

Education Debt Reduction

The EDRP offers debt relief to clinicians in the most difficult to recruit professions, including physicians (generalists and specialists), registered nurses, licensed practical nurses, social workers, and psychologists. The list of difficult to recruit positions is developed annually by VA facilities. Annual reimbursements through the program may be used for tuition and expenses, such as fees, books, supplies, equipment, and other materials. In 2018, through the MISSION Act Section 302, the annual loan repayment was increased from $24,000 to $40,000, and the maximum level of support was increased from $120,000 to $200,000 over 5 years. Recipients receive reimbursement for loan repayment at the end of each year or service period and recipients are not required to remain in VA for 5 years.

Program Results

Health Professions Scholarship

For academic years 2020/2021 and 2021/2022, 126 HPSP applications from both allopathic and osteopathic schools were submitted and 51 scholarships were awarded (Table 3). Assuming an average residency length of 4 years, VHA estimates that these awards will yield 204 service-year equivalents by 2029.

Veterans Healing Veterans

In the VHV program, scholarship recipients came from 5 Teague-Cranston schools; 2 at University of South Carolina, 2 at East Tennessee State University, 2 at Wright State University, 1 at Texas A&M College of Medicine, 1 at Marshall University; and 3 HBCUs; 2 at Howard University, 1 at Morehouse School of Medicine and 1 at Meharry Medical College. The Charles R. Drew University of Medicine and Science did not nominate any students for the scholarship. Assuming all recipients complete postgraduate training, the VHV scholarship program will provide an additional 12 veteran physicians to serve at VA for at least 4 years each (48 service years).

Specialty Education Loan Repayment

Fourteen applicants have been approved, including 5 in psychiatry, 4 in family medicine, 3 in internal medicine, 1 in emergency medicine, and 1 in geriatrics. The mean loan repayment is anticipated to be $110,000 and equating to 38.5 VA service years or a mean of 2.3 years of service obligation per individual for the first cohort. The program has no termination date, and with continued funding, VA anticipates granting 100 loan repayments annually.

Education Debt Reduction

Since 2018, 1,546 VA physicians have received EDRP awards. Due to the increased reimbursement provided through the MISSION Act, average physician award amounts have increased from $96,090 in 2018 to $142,557 in 2019 and $148,302 in 2020.

Conclusions

The VA physician scholarship and loan repayment programs outlined in the MISSION Act build on the success of existing federal scholarship programs by providing opportunities for physician trainees to alleviate educational debt and explore a VA health professions career.

Looking ahead, VA must focus on measuring the success of the MISSION scholarship and loan repayment programs by tracking rates of acceptance and student graduation, residency and fellowship completion, and placement in VA medical facilities—both for the service obligation and future employment. Ultimately, the total impact on VA staffing, especially at rural and underresourced sites, will determine the success of the MISSION programs.

As one of 4 statutory missions, the US Department of Veterans Affairs (VA) educates and trains health professionals to enhance the quality of and timely access to care provided to veterans within the Veterans Health Administration (VHA). To achieve its mission to educate, the VA has conducted health professions education and training in partnership with affiliated US academic institutions for the past 76 years in accordance with the landmark 1946 Policy Memorandum No. 2.^1,2

Despite its long-term success affiliating with medical schools, VA has continued to be challenged by physician staff shortages with wide variability in the number and specialty of available health care professionals across facilities.^3,4 A 2020 VA Office of Inspector General report on VHA occupational staffing shortages concluded that numerous physician specialties were difficult to recruit due to a lack of qualified applicants, noncompetitive salary, and less desirable geographic locations.³

Federal health professions scholarship programs and loan repayment programs have long been used to address physician shortages.⁴ Focusing on physician shortages in underserved areas in the US, the Emergency Health Personnel Act of 1970 and its subsequent amendments paved the way for various federal medical school scholarship and loan repayment programs.⁵ Similarly, physician shortages in the armed forces were mitigated through the Uniformed Services Health Professions Revitalization Act of 1972 (USHPRA).^6,7

In 2018, Congress passed the VA MISSION (Maintaining Internal Systems and Strengthening Integrated Outside Networks) Act, which included sections designed to alleviate physician shortages in the VHA.⁸ These sections authorized scholarships similar to those offered by the US Department of Defense (DoD) and loan repayment programs. Section 301 created the Health Professions Scholarship Program (HPSP), which offers scholarships for physicians and dentists. Section 302 increased the maximum debt reduction through the Education Debt Reduction Program (EDRP). Section 303 authorizes the Specialty Education Loan Repayment Program (SELRP), which provides for repayment of educational loans for physicians in specialties deemed necessary for VA. Finally, Section 304 created the Veterans Healing Veterans (VHV), a pilot scholarship specifically for veteran medical students.
 

Program Characteristics

Health Professions Scholarship

The VA HPSP is a program for physicians and dentists that extends from 2020 to 2033. The HPSP funds the costs of tuition, fees, and provides a stipend with a service obligation of 18 months for each year of support. The program is authorized for 10 years and must provide a minimum of 50 scholarships annually for physicians or dentists based on VHA needs. Applications are screened based on criteria that include a commitment to rural or underserved populations, veteran status, grade point average, essays, and letters of recommendation. Although the minimum required number of scholarships annually is 50, VA anticipates providing 1000 scholarships over 10 years with an aim to significantly increase the number physicians at VHA facilities (Table 1).

Veterans Healing Veterans

Implemented in 2020, the VHV was a 1-year pilot program. It offered scholarships to 2 veterans attending medical school at each of the 5 Teague-Cranston and the 4 Historically Black College and University (HBCU) medical schools (Table 2). The intent of the program was to determine the feasibility of increasing the pool of veteran physicians at VHA. Eligible applicants were notified of the scholarship opportunity through the American Medical College Application Service or through the medical school. Applicants must have separated from military service within the preceding 10 years of being admitted to medical school. In exchange for full tuition, fees, a monthly stipend, and rotation travel costs, the recipients accepted a 4-year clinical service obligation at VA facilities after completing their residency training.

Specialty Education Loan Repayment

The SELRP is a loan repayment program available to recently graduated physicians. Applicants must have graduated from an accredited medical or osteopathic school, matched to an accredited residency program and be ≥ 2 years from completion of residency. The specialties qualifying for SELRP are determined through an analysis of succession planning by the VA Office of Workforce Management and Consulting and change based on VA physician workforce needs. The SELRP provides loan repayment in the amount of $40,000 per year for up to 4 years, with a service obligation of 1 year for each $40,000 of support. In April 2021, VA began accepting applications from the eligible specialties of family medicine, internal medicine, gastroenterology, psychiatry, emergency medicine, and geriatrics.

Education Debt Reduction

The EDRP offers debt relief to clinicians in the most difficult to recruit professions, including physicians (generalists and specialists), registered nurses, licensed practical nurses, social workers, and psychologists. The list of difficult to recruit positions is developed annually by VA facilities. Annual reimbursements through the program may be used for tuition and expenses, such as fees, books, supplies, equipment, and other materials. In 2018, through the MISSION Act Section 302, the annual loan repayment was increased from $24,000 to $40,000, and the maximum level of support was increased from $120,000 to $200,000 over 5 years. Recipients receive reimbursement for loan repayment at the end of each year or service period and recipients are not required to remain in VA for 5 years.

Program Results

Health Professions Scholarship

For academic years 2020/2021 and 2021/2022, 126 HPSP applications from both allopathic and osteopathic schools were submitted and 51 scholarships were awarded (Table 3). Assuming an average residency length of 4 years, VHA estimates that these awards will yield 204 service-year equivalents by 2029.

Veterans Healing Veterans

In the VHV program, scholarship recipients came from 5 Teague-Cranston schools; 2 at University of South Carolina, 2 at East Tennessee State University, 2 at Wright State University, 1 at Texas A&M College of Medicine, 1 at Marshall University; and 3 HBCUs; 2 at Howard University, 1 at Morehouse School of Medicine and 1 at Meharry Medical College. The Charles R. Drew University of Medicine and Science did not nominate any students for the scholarship. Assuming all recipients complete postgraduate training, the VHV scholarship program will provide an additional 12 veteran physicians to serve at VA for at least 4 years each (48 service years).

Specialty Education Loan Repayment

Fourteen applicants have been approved, including 5 in psychiatry, 4 in family medicine, 3 in internal medicine, 1 in emergency medicine, and 1 in geriatrics. The mean loan repayment is anticipated to be $110,000 and equating to 38.5 VA service years or a mean of 2.3 years of service obligation per individual for the first cohort. The program has no termination date, and with continued funding, VA anticipates granting 100 loan repayments annually.

Education Debt Reduction

Since 2018, 1,546 VA physicians have received EDRP awards. Due to the increased reimbursement provided through the MISSION Act, average physician award amounts have increased from $96,090 in 2018 to $142,557 in 2019 and $148,302 in 2020.

Conclusions

The VA physician scholarship and loan repayment programs outlined in the MISSION Act build on the success of existing federal scholarship programs by providing opportunities for physician trainees to alleviate educational debt and explore a VA health professions career.

Looking ahead, VA must focus on measuring the success of the MISSION scholarship and loan repayment programs by tracking rates of acceptance and student graduation, residency and fellowship completion, and placement in VA medical facilities—both for the service obligation and future employment. Ultimately, the total impact on VA staffing, especially at rural and underresourced sites, will determine the success of the MISSION programs.

As one of 4 statutory missions, the US Department of Veterans Affairs (VA) educates and trains health professionals to enhance the quality of and timely access to care provided to veterans within the Veterans Health Administration (VHA). To achieve its mission to educate, the VA has conducted health professions education and training in partnership with affiliated US academic institutions for the past 76 years in accordance with the landmark 1946 Policy Memorandum No. 2.^1,2

Despite its long-term success affiliating with medical schools, VA has continued to be challenged by physician staff shortages with wide variability in the number and specialty of available health care professionals across facilities.^3,4 A 2020 VA Office of Inspector General report on VHA occupational staffing shortages concluded that numerous physician specialties were difficult to recruit due to a lack of qualified applicants, noncompetitive salary, and less desirable geographic locations.³

Federal health professions scholarship programs and loan repayment programs have long been used to address physician shortages.⁴ Focusing on physician shortages in underserved areas in the US, the Emergency Health Personnel Act of 1970 and its subsequent amendments paved the way for various federal medical school scholarship and loan repayment programs.⁵ Similarly, physician shortages in the armed forces were mitigated through the Uniformed Services Health Professions Revitalization Act of 1972 (USHPRA).^6,7

In 2018, Congress passed the VA MISSION (Maintaining Internal Systems and Strengthening Integrated Outside Networks) Act, which included sections designed to alleviate physician shortages in the VHA.⁸ These sections authorized scholarships similar to those offered by the US Department of Defense (DoD) and loan repayment programs. Section 301 created the Health Professions Scholarship Program (HPSP), which offers scholarships for physicians and dentists. Section 302 increased the maximum debt reduction through the Education Debt Reduction Program (EDRP). Section 303 authorizes the Specialty Education Loan Repayment Program (SELRP), which provides for repayment of educational loans for physicians in specialties deemed necessary for VA. Finally, Section 304 created the Veterans Healing Veterans (VHV), a pilot scholarship specifically for veteran medical students.
 

Program Characteristics

Health Professions Scholarship

The VA HPSP is a program for physicians and dentists that extends from 2020 to 2033. The HPSP funds the costs of tuition, fees, and provides a stipend with a service obligation of 18 months for each year of support. The program is authorized for 10 years and must provide a minimum of 50 scholarships annually for physicians or dentists based on VHA needs. Applications are screened based on criteria that include a commitment to rural or underserved populations, veteran status, grade point average, essays, and letters of recommendation. Although the minimum required number of scholarships annually is 50, VA anticipates providing 1000 scholarships over 10 years with an aim to significantly increase the number physicians at VHA facilities (Table 1).

Veterans Healing Veterans

Implemented in 2020, the VHV was a 1-year pilot program. It offered scholarships to 2 veterans attending medical school at each of the 5 Teague-Cranston and the 4 Historically Black College and University (HBCU) medical schools (Table 2). The intent of the program was to determine the feasibility of increasing the pool of veteran physicians at VHA. Eligible applicants were notified of the scholarship opportunity through the American Medical College Application Service or through the medical school. Applicants must have separated from military service within the preceding 10 years of being admitted to medical school. In exchange for full tuition, fees, a monthly stipend, and rotation travel costs, the recipients accepted a 4-year clinical service obligation at VA facilities after completing their residency training.

Specialty Education Loan Repayment

The SELRP is a loan repayment program available to recently graduated physicians. Applicants must have graduated from an accredited medical or osteopathic school, matched to an accredited residency program and be ≥ 2 years from completion of residency. The specialties qualifying for SELRP are determined through an analysis of succession planning by the VA Office of Workforce Management and Consulting and change based on VA physician workforce needs. The SELRP provides loan repayment in the amount of $40,000 per year for up to 4 years, with a service obligation of 1 year for each $40,000 of support. In April 2021, VA began accepting applications from the eligible specialties of family medicine, internal medicine, gastroenterology, psychiatry, emergency medicine, and geriatrics.

Education Debt Reduction

The EDRP offers debt relief to clinicians in the most difficult to recruit professions, including physicians (generalists and specialists), registered nurses, licensed practical nurses, social workers, and psychologists. The list of difficult to recruit positions is developed annually by VA facilities. Annual reimbursements through the program may be used for tuition and expenses, such as fees, books, supplies, equipment, and other materials. In 2018, through the MISSION Act Section 302, the annual loan repayment was increased from $24,000 to $40,000, and the maximum level of support was increased from $120,000 to $200,000 over 5 years. Recipients receive reimbursement for loan repayment at the end of each year or service period and recipients are not required to remain in VA for 5 years.

Program Results

Health Professions Scholarship

For academic years 2020/2021 and 2021/2022, 126 HPSP applications from both allopathic and osteopathic schools were submitted and 51 scholarships were awarded (Table 3). Assuming an average residency length of 4 years, VHA estimates that these awards will yield 204 service-year equivalents by 2029.

Veterans Healing Veterans

In the VHV program, scholarship recipients came from 5 Teague-Cranston schools; 2 at University of South Carolina, 2 at East Tennessee State University, 2 at Wright State University, 1 at Texas A&M College of Medicine, 1 at Marshall University; and 3 HBCUs; 2 at Howard University, 1 at Morehouse School of Medicine and 1 at Meharry Medical College. The Charles R. Drew University of Medicine and Science did not nominate any students for the scholarship. Assuming all recipients complete postgraduate training, the VHV scholarship program will provide an additional 12 veteran physicians to serve at VA for at least 4 years each (48 service years).

Specialty Education Loan Repayment

Fourteen applicants have been approved, including 5 in psychiatry, 4 in family medicine, 3 in internal medicine, 1 in emergency medicine, and 1 in geriatrics. The mean loan repayment is anticipated to be $110,000 and equating to 38.5 VA service years or a mean of 2.3 years of service obligation per individual for the first cohort. The program has no termination date, and with continued funding, VA anticipates granting 100 loan repayments annually.

Education Debt Reduction

Since 2018, 1,546 VA physicians have received EDRP awards. Due to the increased reimbursement provided through the MISSION Act, average physician award amounts have increased from $96,090 in 2018 to $142,557 in 2019 and $148,302 in 2020.

Conclusions

The VA physician scholarship and loan repayment programs outlined in the MISSION Act build on the success of existing federal scholarship programs by providing opportunities for physician trainees to alleviate educational debt and explore a VA health professions career.

Looking ahead, VA must focus on measuring the success of the MISSION scholarship and loan repayment programs by tracking rates of acceptance and student graduation, residency and fellowship completion, and placement in VA medical facilities—both for the service obligation and future employment. Ultimately, the total impact on VA staffing, especially at rural and underresourced sites, will determine the success of the MISSION programs.