Clinical Psychiatry News

President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:

• Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
• Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
• Fox News contributor Janette Nesheiwat, MD, for surgeon general.

Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS). 

Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.

 

Martin A. Makary

Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool. 

As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy. 

Makary is also chief medical officer of telehealth platform Sesame.

Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials. 

In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.

Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”

Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.

In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.

Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.

Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.

While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.

 

Janette Nesheiwat

As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.

She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.

Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith. 

Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”

While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination. 

“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.

 

David J. Weldon

If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.

After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.

He now practices as an internist in Brevard County, Florida.

In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.

Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.” 

But some physicians criticized Weldon for what they called his anti-vaccine views.

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

President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:

• Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
• Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
• Fox News contributor Janette Nesheiwat, MD, for surgeon general.

Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS). 

Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.

 

Martin A. Makary

Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool. 

As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy. 

Makary is also chief medical officer of telehealth platform Sesame.

Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials. 

In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.

Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”

Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.

In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.

Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.

Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.

While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.

 

Janette Nesheiwat

As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.

She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.

Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith. 

Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”

While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination. 

“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.

 

David J. Weldon

If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.

After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.

He now practices as an internist in Brevard County, Florida.

In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.

Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.” 

But some physicians criticized Weldon for what they called his anti-vaccine views.

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

President-elect Donald Trump’s vision for the nation’s top health agencies is coming into focus with three nominations announced Nov. 22 that drew both criticism and praise:

• Surgeon and health researcher Martin A. Makary, MD, MPH, to lead the US Food and Drug Administration (FDA).
• Former Republican congressman and physician David J. Weldon, MD, for director of the US Centers for Disease Control and Prevention (CDC).
• Fox News contributor Janette Nesheiwat, MD, for surgeon general.

Earlier in November, Trump nominated vaccine skeptic and former presidential candidate Robert F. Kennedy Jr. to lead the US Department of Health and Human Services (HHS). 

Here’s what to know about the latest nominees, who, like Kennedy, must be confirmed by the US Senate.

 

Martin A. Makary

Currently a professor at the Johns Hopkins School of Medicine and chief of islet transplant surgery at Johns Hopkins Hospital, Makary co-invented in 2006 a surgery checklist that became a widely-used patient safety tool. 

As a US FDA commissioner, Makary would preside over a $6.5 billion agency with more than 18,000 employees. The agency, part of HHS, oversees human and animal drugs and vaccines, medical devices, food, tobacco and other products. Some of Makary’s views align closely with those of HHS nominee Kennedy. 

Makary is also chief medical officer of telehealth platform Sesame.

Makary was primarily known as a health researcher and author of books about price transparency and the cost of health care until the COVID-19 pandemic, when he became an outspoken critic of the federal response, lambasting restrictions and mandates advocated by the CDC and other public health officials. 

In 2023, Makary told the House Select Subcommittee on the COVID Pandemic that federal officials had ignored what he called “natural immunity.” Studies have shown that natural immunity is “at least as effective as vaccinated immunity, and probably better,” testified Makary.

Makary called for an overhaul of the US FDA in a 2021 Fox News opinion, saying that its culture was “defined by counterproductive rigidity and a refusal to adapt.”

Blind Spots, his most recent book, takes on what he calls “medical dogma” and challenges conventional views on subjects ranging from the microbiome to marijuana to cancer prevention, hormone replacement therapy, antibiotics and peanut allergies.

In an interview he posted to X, Makary blames inappropriate use of antibiotics for a variety of childhood illnesses. He cites increases in obesity, learning disabilities, attention deficit disorder, asthma, celiac disease, ulcerative colitis and Crohn’s disease as all potentially causally related to antibiotics given in childhood.

Makary is an advisor to two conservative think tanks, the Foundation for Research on Equal Opportunity, and to Paragon Health Institute, begun in 2021 by two former top officials in the previous Trump administration.

Makary would “cut the bureaucratic red tape at the agency to make sure Americans get the medical cures and treatments they deserve,” Trump said on his social media platform, Truth Social, and in a press release.

While Los Angeles Times owner and physician-entrepreneur Patrick Soon-Shiong, MBBCh, MSc, praised the nomination of Makary (and the two other nominees) as “inspired,” other physicians criticized Makary for his anti-COVID mandate views and “fear-mongering” over COVID vaccine side effects.

 

Janette Nesheiwat

As surgeon general, Nesheiwat would serve as the top “health communicator in chief” and oversee the 6000 member US Public Health Service Commissioned Corps.

She is a frequent medical contributor to Fox News and serves as a medical director for a group of urgent care clinics in New York. She received her medical degree from the American University of the Caribbean School of Medicine and completed a family medicine residency at the University of Arkansas for Medical Sciences. She is board-certified in family medicine.

Nesheiwat sells vitamin supplements on her website and in December will publish a book on “miracles in medicine” and her Christian faith. 

Trump said in a statement that Nesheiwat “is a fierce advocate and strong communicator for preventive medicine and public health. She is committed to ensuring that Americans have access to affordable, quality healthcare, and believes in empowering individuals to take charge of their health to live longer, healthier lives.”

While Nesheiwat was critical of COVID mandates, she voiced more support for COVID vaccines and mask-wearing during the pandemic than her fellow nominees, leading some Trump supporters to criticize her nomination. 

“A good appointment, happy about this: I got to know @DoctorJanette during the pandemic, exchanging information. She is very smart, thoughtful, interested in learning, and a compassionate doctor, and…a truly nice person,” noted vaccine researcher Peter Hotez, MD, PhD, said on X.

 

David J. Weldon

If confirmed, former congressman Weldon would oversee the sprawling CDC, an agency with a roughly $17 billion budget, 15,000 employees or contractors, and numerous centers covering everything from health statistics to vaccines to epidemiology.

After earning his medical degree from the University at Buffalo School of Medicine, Weldon served in the US Army and US Army reserve. The Republican later served for 14 years in Congress representing Florida’s 15th district, which covers the Tampa region.

He now practices as an internist in Brevard County, Florida.

In Congress, Weldon raised concerns about the safety of some vaccines and promoted the false narrative that a former vaccine ingredient, thimerosal, caused autism, the Washington Post reported. Thimerosal has not been used in child vaccines for more than two decades. He also introduced a bill to move vaccine safety oversight from the CDC to an independent agency within HHS.

Trump said in a statement that Weldon “will proudly restore the CDC to its true purpose, and will work to end the Chronic Disease Epidemic.” 

But some physicians criticized Weldon for what they called his anti-vaccine views.

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

Two Food and Drug Administration (FDA) advisory panels are urging the agency to eliminate the risk management program for the antipsychotic drug clozapine, saying that restrictions are limiting access to a life-changing and life-saving medication for people with schizophrenia.

Members of the Drug Safety and Risk Management and Psychopharmacologic Drugs advisory committees held a joint meeting on November 19 to address whether frequently revised restrictions that have been in place since clozapine was introduced in 1989 should be changed again. Clozapine — the only FDA-approved drug for treatment-resistant schizophrenia — can cause severe neutropenia, so is subject to a Risk Evaluation and Management Strategy (REMS).

Calling the current rules overly burdensome, a majority of committee members voted against continuing a requirement that pharmacies and physicians must provide documentation of a patient’s absolute neutrophil count (ANC) results through the REMS. Monitoring should continue, as directed in the labeling, said the panel.

Panelists also voted overwhelmingly that it is not necessary to mandate physician education about clozapine’s risk of neutropenia and the need for ANC monitoring.

The panel did not vote, however, on whether the REMS should be eliminated altogether. The FDA did not pose that as a voting question for the panels’ consideration.

Following intense lobbying by the American Psychiatric Association (APA), the National Alliance on Mental Illness, and others, the FDA announced in 2022 that the agency would exercise “enforcement discretion” by allowing prescribers and pharmacists to skirt the clozapine REMS rules. But the agency doesn’t know whether the program is meeting its goals, said Tiffany R. Farchione, MD, director of the division of psychiatry at the FDA’s Center for Drug Evaluation and Research.

Among other things, the REMS requires that physicians and pharmacists be certified to prescribe and dispense the drug, that patients be enrolled, and that patient status forms be submitted monthly, showing ANC levels and appropriateness of continuing treatment. 

At the meeting, FDA officials said that 148,000 outpatient clozapine prescriptions were written in 2023. But an estimated 814,000–1.2 million Americans have treatment-resistant schizophrenia, the main indication for clozapine.

“We know the drug is being underutilized,” said Farchione, adding that the agency wants to ensure that physicians and pharmacists “can use the drug, use it safely and help the patients who need it.” 

 

REMS a ‘Hindrance’

As reported by this news organization, research presented earlier this year at the APA annual meeting showed that the risk of moderate and severe neutropenia is low to minimal in people taking clozapine for treatment-resistant schizophrenia. Those findings prompted the study’s investigators to suggest clozapine REMS should be reconsidered.

In the November 19th committee meeting, many panelists said that clozapine was no more dangerous than many antipsychotics and that the administrative requirements were preventing clinicians from prescribing.

“I have fantasized for years about abolishing the clozapine REMS,” said Jacob S. Ballon, MD, MPH, a temporary panel member and associate professor of psychiatry at Stanford University in California.

Panelists Jess Fiedorowicz, MD, PhD, professor and senior research chair in adult psychiatry at the University of Ottawa, Canada; Megan J. Ehret, PharmD, MS, a panelist and professor at the University of Maryland School of Pharmacy, Baltimore; and Rajesh Narendran, MD, a professor in radiology and psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania, agreed.

“I strongly feel that the REMS at this point is just a hindrance,” Narendran said. “I think you should get rid of the REMS.”

However, panelist Walter Dunn, MD, PhD, staff psychiatrist at the VA Greater Los Angeles Healthcare System, cautioned that modifying or eliminating the REMS might not necessarily increase prescribers. If monitoring ANC levels is still recommended in labeling, clinicians will still regard it as the standard of care, said Dunn. And “there are a whole host of other issues associated with clozapine,” that he said were “more concerning.” 

Many patients are accessing clozapine without going through the REMS, which is also of concern to the FDA and drug manufacturers. 

“We estimate about 42,000 patients are not participating in the REMS, said James Shamp, VP of data intelligence and program analytics at United BioSource, a company that supports drug makers.

Leah Hart, PharmD, a risk management analyst with the FDA, told the panel that the agency estimates that 25%-35% of patients taking clozapine may not be participating in the REMS. 

“Today, prescribers, pharmacies, and patients do not have to participate in the REMS in order patients to obtain clozapine,” Hart said.

 

Public Testimony Sways Panel

But psychiatrists, pharmacists, families, and patients who testified during the 90-minute open portion of the meeting disagreed with that assessment, saying the REMS program had a devastatingly chilling effect on clozapine access.

Patty Taggart of Las Vegas said her daughter had nine suicide attempts over the past 14 years, while having tried eight different antipsychotics. In August, after the most-recent attempt, Taggart begged the psychiatrist to prescribe clozapine to her daughter. The clinician refused, citing the REMS. After her daughter’s discharge, Taggart said she found another provider who would prescribe the medication.

Lisa Castellanos said her son Daniel had been treated with a variety of antipsychotics but denied clozapine until he was arrested in 2012 for assault during a psychotic break. The state used the medication to improve Daniel’s mental state so he could stand trial. But when he went to jail after accepting a plea deal, the prison stopped the clozapine. Daniel has since deteriorated and was recently ruled ineligible for parole.

Patients and families also described being rejected at pharmacies — most of which, despite the FDA’s supposed “enforcement discretion” continue to rigorously follow REMS requirements. 

Many panelists said they were moved by patients and family testimony. A dozen or more members of the public were wearing black t-shirts with white writing that declared: “Clozapine is the safest antipsychotic in the world.” 

 

‘Blood-for-Drug Program’

Brian Barnett, MD, director of the psychiatric treatment-resistance program at the Cleveland Clinic in Ohio, said during the public portion of the meeting that “many pharmacies simply refuse to dispense clozapine likely because of the administrative burden and lack of financial incentives.” 

Others want faxed lab results even when the results have been filed electronically, he said. “One of the most dangerous features of the current REMS system is its inflexibility, driven by the so-called ‘no blood, no drug’ ethos which has been baked into the minds of America’s pharmacists.”

“This is a blood-for-drug program,” agreed Rachel Strieff of Tempe, Arizona, who noted that her advocacy group, Angry Moms, and others had submitted 4,000 signatures calling for the end of the REMS. “The largest category of patients harmed by the clozapine REMS have never taken a single dose,” she said, noting that millions of eligible individuals are not getting the drug.

Panel chair James Floyd, MD, professor of medicine at the University of Washington, Seattle, said the public testimony was “very moving.” Families and patients had described “the intensity of suffering that people go through prior to getting to clozapine,” he added.

“We have to listen to that,” said Floyd.


“I want you to know that we hear you,” said Farchione. “We’re here today because of you and your loved ones. And your stories are important, and your experience is important, and what you’ve shared today will have an impact on regulatory decision making.”

While the FDA typically follows its panels’ advice, it’s unclear if the agency will do so for clozapine REMS or when it will release its final decision.

A version of this article appeared on Medscape.com.

Two Food and Drug Administration (FDA) advisory panels are urging the agency to eliminate the risk management program for the antipsychotic drug clozapine, saying that restrictions are limiting access to a life-changing and life-saving medication for people with schizophrenia.

Members of the Drug Safety and Risk Management and Psychopharmacologic Drugs advisory committees held a joint meeting on November 19 to address whether frequently revised restrictions that have been in place since clozapine was introduced in 1989 should be changed again. Clozapine — the only FDA-approved drug for treatment-resistant schizophrenia — can cause severe neutropenia, so is subject to a Risk Evaluation and Management Strategy (REMS).

Calling the current rules overly burdensome, a majority of committee members voted against continuing a requirement that pharmacies and physicians must provide documentation of a patient’s absolute neutrophil count (ANC) results through the REMS. Monitoring should continue, as directed in the labeling, said the panel.

Panelists also voted overwhelmingly that it is not necessary to mandate physician education about clozapine’s risk of neutropenia and the need for ANC monitoring.

The panel did not vote, however, on whether the REMS should be eliminated altogether. The FDA did not pose that as a voting question for the panels’ consideration.

Following intense lobbying by the American Psychiatric Association (APA), the National Alliance on Mental Illness, and others, the FDA announced in 2022 that the agency would exercise “enforcement discretion” by allowing prescribers and pharmacists to skirt the clozapine REMS rules. But the agency doesn’t know whether the program is meeting its goals, said Tiffany R. Farchione, MD, director of the division of psychiatry at the FDA’s Center for Drug Evaluation and Research.

Among other things, the REMS requires that physicians and pharmacists be certified to prescribe and dispense the drug, that patients be enrolled, and that patient status forms be submitted monthly, showing ANC levels and appropriateness of continuing treatment. 

At the meeting, FDA officials said that 148,000 outpatient clozapine prescriptions were written in 2023. But an estimated 814,000–1.2 million Americans have treatment-resistant schizophrenia, the main indication for clozapine.

“We know the drug is being underutilized,” said Farchione, adding that the agency wants to ensure that physicians and pharmacists “can use the drug, use it safely and help the patients who need it.” 

 

REMS a ‘Hindrance’

As reported by this news organization, research presented earlier this year at the APA annual meeting showed that the risk of moderate and severe neutropenia is low to minimal in people taking clozapine for treatment-resistant schizophrenia. Those findings prompted the study’s investigators to suggest clozapine REMS should be reconsidered.

In the November 19th committee meeting, many panelists said that clozapine was no more dangerous than many antipsychotics and that the administrative requirements were preventing clinicians from prescribing.

“I have fantasized for years about abolishing the clozapine REMS,” said Jacob S. Ballon, MD, MPH, a temporary panel member and associate professor of psychiatry at Stanford University in California.

Panelists Jess Fiedorowicz, MD, PhD, professor and senior research chair in adult psychiatry at the University of Ottawa, Canada; Megan J. Ehret, PharmD, MS, a panelist and professor at the University of Maryland School of Pharmacy, Baltimore; and Rajesh Narendran, MD, a professor in radiology and psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania, agreed.

“I strongly feel that the REMS at this point is just a hindrance,” Narendran said. “I think you should get rid of the REMS.”

However, panelist Walter Dunn, MD, PhD, staff psychiatrist at the VA Greater Los Angeles Healthcare System, cautioned that modifying or eliminating the REMS might not necessarily increase prescribers. If monitoring ANC levels is still recommended in labeling, clinicians will still regard it as the standard of care, said Dunn. And “there are a whole host of other issues associated with clozapine,” that he said were “more concerning.” 

Many patients are accessing clozapine without going through the REMS, which is also of concern to the FDA and drug manufacturers. 

“We estimate about 42,000 patients are not participating in the REMS, said James Shamp, VP of data intelligence and program analytics at United BioSource, a company that supports drug makers.

Leah Hart, PharmD, a risk management analyst with the FDA, told the panel that the agency estimates that 25%-35% of patients taking clozapine may not be participating in the REMS. 

“Today, prescribers, pharmacies, and patients do not have to participate in the REMS in order patients to obtain clozapine,” Hart said.

 

Public Testimony Sways Panel

But psychiatrists, pharmacists, families, and patients who testified during the 90-minute open portion of the meeting disagreed with that assessment, saying the REMS program had a devastatingly chilling effect on clozapine access.

Patty Taggart of Las Vegas said her daughter had nine suicide attempts over the past 14 years, while having tried eight different antipsychotics. In August, after the most-recent attempt, Taggart begged the psychiatrist to prescribe clozapine to her daughter. The clinician refused, citing the REMS. After her daughter’s discharge, Taggart said she found another provider who would prescribe the medication.

Lisa Castellanos said her son Daniel had been treated with a variety of antipsychotics but denied clozapine until he was arrested in 2012 for assault during a psychotic break. The state used the medication to improve Daniel’s mental state so he could stand trial. But when he went to jail after accepting a plea deal, the prison stopped the clozapine. Daniel has since deteriorated and was recently ruled ineligible for parole.

Patients and families also described being rejected at pharmacies — most of which, despite the FDA’s supposed “enforcement discretion” continue to rigorously follow REMS requirements. 

Many panelists said they were moved by patients and family testimony. A dozen or more members of the public were wearing black t-shirts with white writing that declared: “Clozapine is the safest antipsychotic in the world.” 

 

‘Blood-for-Drug Program’

Brian Barnett, MD, director of the psychiatric treatment-resistance program at the Cleveland Clinic in Ohio, said during the public portion of the meeting that “many pharmacies simply refuse to dispense clozapine likely because of the administrative burden and lack of financial incentives.” 

Others want faxed lab results even when the results have been filed electronically, he said. “One of the most dangerous features of the current REMS system is its inflexibility, driven by the so-called ‘no blood, no drug’ ethos which has been baked into the minds of America’s pharmacists.”

“This is a blood-for-drug program,” agreed Rachel Strieff of Tempe, Arizona, who noted that her advocacy group, Angry Moms, and others had submitted 4,000 signatures calling for the end of the REMS. “The largest category of patients harmed by the clozapine REMS have never taken a single dose,” she said, noting that millions of eligible individuals are not getting the drug.

Panel chair James Floyd, MD, professor of medicine at the University of Washington, Seattle, said the public testimony was “very moving.” Families and patients had described “the intensity of suffering that people go through prior to getting to clozapine,” he added.

“We have to listen to that,” said Floyd.


“I want you to know that we hear you,” said Farchione. “We’re here today because of you and your loved ones. And your stories are important, and your experience is important, and what you’ve shared today will have an impact on regulatory decision making.”

While the FDA typically follows its panels’ advice, it’s unclear if the agency will do so for clozapine REMS or when it will release its final decision.

A version of this article appeared on Medscape.com.

Two Food and Drug Administration (FDA) advisory panels are urging the agency to eliminate the risk management program for the antipsychotic drug clozapine, saying that restrictions are limiting access to a life-changing and life-saving medication for people with schizophrenia.

Members of the Drug Safety and Risk Management and Psychopharmacologic Drugs advisory committees held a joint meeting on November 19 to address whether frequently revised restrictions that have been in place since clozapine was introduced in 1989 should be changed again. Clozapine — the only FDA-approved drug for treatment-resistant schizophrenia — can cause severe neutropenia, so is subject to a Risk Evaluation and Management Strategy (REMS).

Calling the current rules overly burdensome, a majority of committee members voted against continuing a requirement that pharmacies and physicians must provide documentation of a patient’s absolute neutrophil count (ANC) results through the REMS. Monitoring should continue, as directed in the labeling, said the panel.

Panelists also voted overwhelmingly that it is not necessary to mandate physician education about clozapine’s risk of neutropenia and the need for ANC monitoring.

The panel did not vote, however, on whether the REMS should be eliminated altogether. The FDA did not pose that as a voting question for the panels’ consideration.

Following intense lobbying by the American Psychiatric Association (APA), the National Alliance on Mental Illness, and others, the FDA announced in 2022 that the agency would exercise “enforcement discretion” by allowing prescribers and pharmacists to skirt the clozapine REMS rules. But the agency doesn’t know whether the program is meeting its goals, said Tiffany R. Farchione, MD, director of the division of psychiatry at the FDA’s Center for Drug Evaluation and Research.

Among other things, the REMS requires that physicians and pharmacists be certified to prescribe and dispense the drug, that patients be enrolled, and that patient status forms be submitted monthly, showing ANC levels and appropriateness of continuing treatment. 

At the meeting, FDA officials said that 148,000 outpatient clozapine prescriptions were written in 2023. But an estimated 814,000–1.2 million Americans have treatment-resistant schizophrenia, the main indication for clozapine.

“We know the drug is being underutilized,” said Farchione, adding that the agency wants to ensure that physicians and pharmacists “can use the drug, use it safely and help the patients who need it.” 

 

REMS a ‘Hindrance’

As reported by this news organization, research presented earlier this year at the APA annual meeting showed that the risk of moderate and severe neutropenia is low to minimal in people taking clozapine for treatment-resistant schizophrenia. Those findings prompted the study’s investigators to suggest clozapine REMS should be reconsidered.

In the November 19th committee meeting, many panelists said that clozapine was no more dangerous than many antipsychotics and that the administrative requirements were preventing clinicians from prescribing.

“I have fantasized for years about abolishing the clozapine REMS,” said Jacob S. Ballon, MD, MPH, a temporary panel member and associate professor of psychiatry at Stanford University in California.

Panelists Jess Fiedorowicz, MD, PhD, professor and senior research chair in adult psychiatry at the University of Ottawa, Canada; Megan J. Ehret, PharmD, MS, a panelist and professor at the University of Maryland School of Pharmacy, Baltimore; and Rajesh Narendran, MD, a professor in radiology and psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania, agreed.

“I strongly feel that the REMS at this point is just a hindrance,” Narendran said. “I think you should get rid of the REMS.”

However, panelist Walter Dunn, MD, PhD, staff psychiatrist at the VA Greater Los Angeles Healthcare System, cautioned that modifying or eliminating the REMS might not necessarily increase prescribers. If monitoring ANC levels is still recommended in labeling, clinicians will still regard it as the standard of care, said Dunn. And “there are a whole host of other issues associated with clozapine,” that he said were “more concerning.” 

Many patients are accessing clozapine without going through the REMS, which is also of concern to the FDA and drug manufacturers. 

“We estimate about 42,000 patients are not participating in the REMS, said James Shamp, VP of data intelligence and program analytics at United BioSource, a company that supports drug makers.

Leah Hart, PharmD, a risk management analyst with the FDA, told the panel that the agency estimates that 25%-35% of patients taking clozapine may not be participating in the REMS. 

“Today, prescribers, pharmacies, and patients do not have to participate in the REMS in order patients to obtain clozapine,” Hart said.

 

Public Testimony Sways Panel

But psychiatrists, pharmacists, families, and patients who testified during the 90-minute open portion of the meeting disagreed with that assessment, saying the REMS program had a devastatingly chilling effect on clozapine access.

Patty Taggart of Las Vegas said her daughter had nine suicide attempts over the past 14 years, while having tried eight different antipsychotics. In August, after the most-recent attempt, Taggart begged the psychiatrist to prescribe clozapine to her daughter. The clinician refused, citing the REMS. After her daughter’s discharge, Taggart said she found another provider who would prescribe the medication.

Lisa Castellanos said her son Daniel had been treated with a variety of antipsychotics but denied clozapine until he was arrested in 2012 for assault during a psychotic break. The state used the medication to improve Daniel’s mental state so he could stand trial. But when he went to jail after accepting a plea deal, the prison stopped the clozapine. Daniel has since deteriorated and was recently ruled ineligible for parole.

Patients and families also described being rejected at pharmacies — most of which, despite the FDA’s supposed “enforcement discretion” continue to rigorously follow REMS requirements. 

Many panelists said they were moved by patients and family testimony. A dozen or more members of the public were wearing black t-shirts with white writing that declared: “Clozapine is the safest antipsychotic in the world.” 

 

‘Blood-for-Drug Program’

Brian Barnett, MD, director of the psychiatric treatment-resistance program at the Cleveland Clinic in Ohio, said during the public portion of the meeting that “many pharmacies simply refuse to dispense clozapine likely because of the administrative burden and lack of financial incentives.” 

Others want faxed lab results even when the results have been filed electronically, he said. “One of the most dangerous features of the current REMS system is its inflexibility, driven by the so-called ‘no blood, no drug’ ethos which has been baked into the minds of America’s pharmacists.”

“This is a blood-for-drug program,” agreed Rachel Strieff of Tempe, Arizona, who noted that her advocacy group, Angry Moms, and others had submitted 4,000 signatures calling for the end of the REMS. “The largest category of patients harmed by the clozapine REMS have never taken a single dose,” she said, noting that millions of eligible individuals are not getting the drug.

Panel chair James Floyd, MD, professor of medicine at the University of Washington, Seattle, said the public testimony was “very moving.” Families and patients had described “the intensity of suffering that people go through prior to getting to clozapine,” he added.

“We have to listen to that,” said Floyd.


“I want you to know that we hear you,” said Farchione. “We’re here today because of you and your loved ones. And your stories are important, and your experience is important, and what you’ve shared today will have an impact on regulatory decision making.”

While the FDA typically follows its panels’ advice, it’s unclear if the agency will do so for clozapine REMS or when it will release its final decision.

A version of this article appeared on Medscape.com.

Suicide and self-harm continue to be serious concerns in Europe, despite decreasing rates over the past two decades. In 2021 alone, 47,346 people died by suicide in the European Union, close to 1% of all deaths reported that year. Measures have been taken at population, subpopulation, and individual levels to prevent suicide and suicide attempts. But can more be done? Yes, according to experts.

Researchers are investigating factors that contribute to suicide at the individual level, as well as environmental and societal pressures that may increase risk. New predictive tools show promise in identifying individuals at high risk, and ongoing programs offer hope for early and ongoing interventions. Successful preventive strategies are multimodal, emphasizing the need for trained primary care and mental health professionals to work together to identify and support individuals at risk at every age and in all settings.

 

‘Radical Change’ Needed

The medical community’s approach to suicide prevention is all wrong, according to Igor Galynker, MD, PhD, clinical professor of psychiatry and director of the Mount Sinai Suicide Prevention Research Lab in New York City. 

Galynker is collaborating with colleagues in various parts of the world, including Europe, to validate the use of suicide crisis syndrome (SCS) as a diagnosis to help imminent suicide risk evaluation and treatment.

SCS is a negative cognitive-affective state associated with imminent suicidal behavior in those who are already at high risk for suicide. Galynker and his colleagues want to see SCS recognized and accepted as a suicide-specific diagnosis in the Diagnostic and Statistical Manual of Mental Disorders and the World Health Organization’s International Classification of Diseases. 

Currently, he explained to this news organization, clinicians depend on a person at risk for suicide telling them that this is what they are feeling. This is “absurd,” he said, because people in this situation are in acute pain and distress and cannot answer accurately.

“It is the most lethal psychiatric condition, because people die from it ... yet we rely on people at the worst moment of their lives to tell us accurately when and how they are going to kill themselves. We don’t ask people with serious mental illness to diagnose their own mental illness and rely on that diagnosis.”

Data show that most people who attempt or die by suicide deny suicidal thoughts when assessed by healthcare providers using current questionnaires and scales. Thus, there needs to be “a radical change” in how patients at acute risk are assessed and treated to help “prevent suicides and avoid lost opportunities to intervene,” he said.

Galynker explained that SCS is the final and most acute stage of the “ narrative crisis model” of suicide, which reflects the progression of suicidal risk from chronic risk factors to imminent suicidal risk. “The narrative crisis model has four distinct and successive stages, with specific guidance and applicable interventions that enable patients to receive a stage-specific treatment.”

“Suicide crisis syndrome is a very treatable syndrome that rapidly resolves” with appropriate interventions, he said. “Once it is treated, the patient can engage with psychotherapy and other treatments.”

Galynker said he and his colleagues have had encouraging results with their studies so far on the subjective and objective views of clinicians using the risk assessment tools they are developing to assess suicidal ideation. Further studies are ongoing. 

 

Improving Prediction

There is definitely room for improvement in current approaches to suicide prevention, said Raffaella Calati, PhD, assistant professor of clinical psychology at the University of Milano-Bicocca, Italy, who has had research collaborations with Galynker.

Calati advocates for a more integrated approach across disciplines, institutions, and the community to provide an effective support network for those at risk. 

Accurately predicting suicide risk is challenging, she told this news organization. She and colleagues are working to develop more precise predictive tools for identifying individuals at risk, often by leveraging artificial intelligence and data analytics. They have designed and implemented app-based interventions for psychiatric patients at risk for suicide and university students with psychological distress. The interventions are personalized and based on multiple approaches, such as cognitive-behavioral therapy (CBT) and third-wave CBT. 

The results of current studies are preliminary, she acknowledged, “but even if apps are extremely complex, our projects received high interest from participants and the scientific community,” she said. The aim now is to integrate these tools into healthcare systems so that monitoring high-risk patients becomes part of regular care. 

Another area of focus is the identification of specific subtypes of individuals at risk for suicide, particularly by examining factors such as pain, dissociation, and interoception — the ability to sense and interpret internal signals from the body. 

“By understanding how these experiences intersect and contribute to suicide risk, I aim to identify distinct profiles within at-risk populations, which could ultimately enable more tailored and effective prevention efforts,” she said.

Her work also involves meta-research to build large, comprehensive datasets that increase statistical power for exploring suicide risk factors, such as physical health conditions and symptoms associated with borderline personality disorder. By creating these datasets, she aims to “improve understanding of how various factors contribute to suicide risk, ultimately supporting more effective prevention strategies.”

 

Country-Level Efforts

Preventive work is underway in other countries as well. In Nordic countries such as Denmark, Finland, and Sweden, large-scale national registries that track people’s medical histories, prescriptions, and demographic information are being used to develop predictive algorithms that identify those at high risk for suicide. The predictions are based on known risk factors like previous mental health diagnoses, substance abuse, and social determinants of health.

A recent Norwegian study found that a novel assessment tool used at admission to an acute inpatient unit was a powerful predictor of suicide within 3 years post-discharge.

Researchers in the Netherlands have also recently co-designed a digital integrated suicide prevention program, which has led to a significant reduction in suicide mortality. 

SUPREMOCOL (suicide prevention by monitoring and collaborative care) was implemented in Noord-Brabant, a province in the Netherlands that historically had high suicide rates. It combines technology and personal care, allowing healthcare providers to track a person’s mental health, including by phone calls, text messages, and mobile apps that help people express their feelings and report any changes in their mental state. By staying connected, the program aims to identify warning signs early and provide timely interventions.

The results from the 5-year project showed that rates dropped by 21.5%, from 14.4 per 100,000 to 11.8 per 100,000, and remained low, with a rate of 11.3 per 100,000 by 2021.

Finland used to have one of the highest suicide rates in the world. Now it is implementing its suicide prevention program for 2020-2030, with 36 proposed measures to prevent suicide mortality. 

The program includes measures such as increasing public awareness, early intervention, supporting at-risk groups, developing new treatment options, and enhancing research efforts. Earlier successful interventions included limiting access to firearms and poison, and increasing use of antidepressants and other targeted interventions.

“A key is to ensure that the individuals at risk of suicide have access to adequate, timely, and evidence-based care,” said Timo Partonen, MD, research professor at the Finnish Institute for Health and Welfare and associate professor of psychiatry at the University of Helsinki.

“Emergency and frontline professionals, as well as general practitioners and occupational health physicians, have a key role in identifying people at risk of suicide,” he noted. “High-quality competencies will be developed for healthcare professionals, including access to evidence-based suicide prevention models for addressing and assessing suicide risk.” 

 

Global Strategies

Policymakers across Europe are increasingly recognizing the importance of enhanced public health approaches to suicide prevention. 

The recently adopted EU Action Plan on Mental Health emphasizes the need for comprehensive suicide prevention strategies across Europe, including the promotion of mental health literacy and the provision of accessible mental health services.

The plan was informed by initiatives such as the European Alliance Against Depression (EAAD)-Best project, which ran from 2021 until March 2024. The collaborative project brought together researchers, healthcare providers, and community organizations to improve care for patients with depression and to prevent suicidal behavior in Europe. 

The multimodal approach included community engagement and training for healthcare professionals, as well as promoting the international uptake of the iFightDepression tool, an internet-based self-management approach for patients with depression. It has shown promise in reducing suicide rates in participating regions, including Europe, Australia, South America, and Africa.

“What we now know is that multiple interventions produce a synergic effect with a tendency to reduce suicidal behavior,” said EAAD founding member Ricardo Gusmão, MD, PhD, professor of public mental health at the University of Porto, Portugal. Current approaches to suicide prevention globally vary widely, with “many, fragmentary, atomized interventions, and we know that none of them, in isolation, produces spectacular results.” 

Gusmão explained that promising national suicide prevention strategies are based on multicomponent community interventions. On the clinical side, they encompass training primary health and specialized mental health professionals, and have a guaranteed chain of care and functioning pathways for access. They also involve educational programs in schools, universities, prisons, work settings, and geriatric care centers. Additionally, they have well-developed good standards for media communication and health marketing campaigns on well-being and mental health literacy.

Relevant and cohesive themes for successful strategies include the promotion of positive mental health, the identification and available treatments for depression and common mental disorders, and the management of suicidal crisis stigma. 

“We are now focusing on workplace settings and vulnerable groups such as youth, the elderly, unemployed, migrants and, of course, people affected by mental disorders,” he said. “Suicide prevention is like a web that must be weaved by long-lasting efforts and intersectoral collaboration.”

“Even one suicide is one too many,” Brendan Kelly, MD, PhD, professor of psychiatry, Trinity College Dublin, and author of The Modern Psychiatrist’s Guide to Contemporary Practice, told this news organization. “Nobody is born wanting to die by suicide. And every suicide is an individual tragedy, not a statistic. We need to work ever more intensively to reduce rates of suicide. All contributions to research and fresh thinking are welcome.”

Galynker, Calati, Partonen, and Kelly have disclosed no relevant financial relationships.  Gusmão has been involved in organizing Janssen-funded trainings for registrars on suicidal crisis management. 

 

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

Suicide and self-harm continue to be serious concerns in Europe, despite decreasing rates over the past two decades. In 2021 alone, 47,346 people died by suicide in the European Union, close to 1% of all deaths reported that year. Measures have been taken at population, subpopulation, and individual levels to prevent suicide and suicide attempts. But can more be done? Yes, according to experts.

Researchers are investigating factors that contribute to suicide at the individual level, as well as environmental and societal pressures that may increase risk. New predictive tools show promise in identifying individuals at high risk, and ongoing programs offer hope for early and ongoing interventions. Successful preventive strategies are multimodal, emphasizing the need for trained primary care and mental health professionals to work together to identify and support individuals at risk at every age and in all settings.

 

‘Radical Change’ Needed

The medical community’s approach to suicide prevention is all wrong, according to Igor Galynker, MD, PhD, clinical professor of psychiatry and director of the Mount Sinai Suicide Prevention Research Lab in New York City. 

Galynker is collaborating with colleagues in various parts of the world, including Europe, to validate the use of suicide crisis syndrome (SCS) as a diagnosis to help imminent suicide risk evaluation and treatment.

SCS is a negative cognitive-affective state associated with imminent suicidal behavior in those who are already at high risk for suicide. Galynker and his colleagues want to see SCS recognized and accepted as a suicide-specific diagnosis in the Diagnostic and Statistical Manual of Mental Disorders and the World Health Organization’s International Classification of Diseases. 

Currently, he explained to this news organization, clinicians depend on a person at risk for suicide telling them that this is what they are feeling. This is “absurd,” he said, because people in this situation are in acute pain and distress and cannot answer accurately.

“It is the most lethal psychiatric condition, because people die from it ... yet we rely on people at the worst moment of their lives to tell us accurately when and how they are going to kill themselves. We don’t ask people with serious mental illness to diagnose their own mental illness and rely on that diagnosis.”

Data show that most people who attempt or die by suicide deny suicidal thoughts when assessed by healthcare providers using current questionnaires and scales. Thus, there needs to be “a radical change” in how patients at acute risk are assessed and treated to help “prevent suicides and avoid lost opportunities to intervene,” he said.

Galynker explained that SCS is the final and most acute stage of the “ narrative crisis model” of suicide, which reflects the progression of suicidal risk from chronic risk factors to imminent suicidal risk. “The narrative crisis model has four distinct and successive stages, with specific guidance and applicable interventions that enable patients to receive a stage-specific treatment.”

“Suicide crisis syndrome is a very treatable syndrome that rapidly resolves” with appropriate interventions, he said. “Once it is treated, the patient can engage with psychotherapy and other treatments.”

Galynker said he and his colleagues have had encouraging results with their studies so far on the subjective and objective views of clinicians using the risk assessment tools they are developing to assess suicidal ideation. Further studies are ongoing. 

 

Improving Prediction

There is definitely room for improvement in current approaches to suicide prevention, said Raffaella Calati, PhD, assistant professor of clinical psychology at the University of Milano-Bicocca, Italy, who has had research collaborations with Galynker.

Calati advocates for a more integrated approach across disciplines, institutions, and the community to provide an effective support network for those at risk. 

Accurately predicting suicide risk is challenging, she told this news organization. She and colleagues are working to develop more precise predictive tools for identifying individuals at risk, often by leveraging artificial intelligence and data analytics. They have designed and implemented app-based interventions for psychiatric patients at risk for suicide and university students with psychological distress. The interventions are personalized and based on multiple approaches, such as cognitive-behavioral therapy (CBT) and third-wave CBT. 

The results of current studies are preliminary, she acknowledged, “but even if apps are extremely complex, our projects received high interest from participants and the scientific community,” she said. The aim now is to integrate these tools into healthcare systems so that monitoring high-risk patients becomes part of regular care. 

Another area of focus is the identification of specific subtypes of individuals at risk for suicide, particularly by examining factors such as pain, dissociation, and interoception — the ability to sense and interpret internal signals from the body. 

“By understanding how these experiences intersect and contribute to suicide risk, I aim to identify distinct profiles within at-risk populations, which could ultimately enable more tailored and effective prevention efforts,” she said.

Her work also involves meta-research to build large, comprehensive datasets that increase statistical power for exploring suicide risk factors, such as physical health conditions and symptoms associated with borderline personality disorder. By creating these datasets, she aims to “improve understanding of how various factors contribute to suicide risk, ultimately supporting more effective prevention strategies.”

 

Country-Level Efforts

Preventive work is underway in other countries as well. In Nordic countries such as Denmark, Finland, and Sweden, large-scale national registries that track people’s medical histories, prescriptions, and demographic information are being used to develop predictive algorithms that identify those at high risk for suicide. The predictions are based on known risk factors like previous mental health diagnoses, substance abuse, and social determinants of health.

A recent Norwegian study found that a novel assessment tool used at admission to an acute inpatient unit was a powerful predictor of suicide within 3 years post-discharge.

Researchers in the Netherlands have also recently co-designed a digital integrated suicide prevention program, which has led to a significant reduction in suicide mortality. 

SUPREMOCOL (suicide prevention by monitoring and collaborative care) was implemented in Noord-Brabant, a province in the Netherlands that historically had high suicide rates. It combines technology and personal care, allowing healthcare providers to track a person’s mental health, including by phone calls, text messages, and mobile apps that help people express their feelings and report any changes in their mental state. By staying connected, the program aims to identify warning signs early and provide timely interventions.

The results from the 5-year project showed that rates dropped by 21.5%, from 14.4 per 100,000 to 11.8 per 100,000, and remained low, with a rate of 11.3 per 100,000 by 2021.

Finland used to have one of the highest suicide rates in the world. Now it is implementing its suicide prevention program for 2020-2030, with 36 proposed measures to prevent suicide mortality. 

The program includes measures such as increasing public awareness, early intervention, supporting at-risk groups, developing new treatment options, and enhancing research efforts. Earlier successful interventions included limiting access to firearms and poison, and increasing use of antidepressants and other targeted interventions.

“A key is to ensure that the individuals at risk of suicide have access to adequate, timely, and evidence-based care,” said Timo Partonen, MD, research professor at the Finnish Institute for Health and Welfare and associate professor of psychiatry at the University of Helsinki.

“Emergency and frontline professionals, as well as general practitioners and occupational health physicians, have a key role in identifying people at risk of suicide,” he noted. “High-quality competencies will be developed for healthcare professionals, including access to evidence-based suicide prevention models for addressing and assessing suicide risk.” 

 

Global Strategies

Policymakers across Europe are increasingly recognizing the importance of enhanced public health approaches to suicide prevention. 

The recently adopted EU Action Plan on Mental Health emphasizes the need for comprehensive suicide prevention strategies across Europe, including the promotion of mental health literacy and the provision of accessible mental health services.

The plan was informed by initiatives such as the European Alliance Against Depression (EAAD)-Best project, which ran from 2021 until March 2024. The collaborative project brought together researchers, healthcare providers, and community organizations to improve care for patients with depression and to prevent suicidal behavior in Europe. 

The multimodal approach included community engagement and training for healthcare professionals, as well as promoting the international uptake of the iFightDepression tool, an internet-based self-management approach for patients with depression. It has shown promise in reducing suicide rates in participating regions, including Europe, Australia, South America, and Africa.

“What we now know is that multiple interventions produce a synergic effect with a tendency to reduce suicidal behavior,” said EAAD founding member Ricardo Gusmão, MD, PhD, professor of public mental health at the University of Porto, Portugal. Current approaches to suicide prevention globally vary widely, with “many, fragmentary, atomized interventions, and we know that none of them, in isolation, produces spectacular results.” 

Gusmão explained that promising national suicide prevention strategies are based on multicomponent community interventions. On the clinical side, they encompass training primary health and specialized mental health professionals, and have a guaranteed chain of care and functioning pathways for access. They also involve educational programs in schools, universities, prisons, work settings, and geriatric care centers. Additionally, they have well-developed good standards for media communication and health marketing campaigns on well-being and mental health literacy.

Relevant and cohesive themes for successful strategies include the promotion of positive mental health, the identification and available treatments for depression and common mental disorders, and the management of suicidal crisis stigma. 

“We are now focusing on workplace settings and vulnerable groups such as youth, the elderly, unemployed, migrants and, of course, people affected by mental disorders,” he said. “Suicide prevention is like a web that must be weaved by long-lasting efforts and intersectoral collaboration.”

“Even one suicide is one too many,” Brendan Kelly, MD, PhD, professor of psychiatry, Trinity College Dublin, and author of The Modern Psychiatrist’s Guide to Contemporary Practice, told this news organization. “Nobody is born wanting to die by suicide. And every suicide is an individual tragedy, not a statistic. We need to work ever more intensively to reduce rates of suicide. All contributions to research and fresh thinking are welcome.”

Galynker, Calati, Partonen, and Kelly have disclosed no relevant financial relationships.  Gusmão has been involved in organizing Janssen-funded trainings for registrars on suicidal crisis management. 

 

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

Suicide and self-harm continue to be serious concerns in Europe, despite decreasing rates over the past two decades. In 2021 alone, 47,346 people died by suicide in the European Union, close to 1% of all deaths reported that year. Measures have been taken at population, subpopulation, and individual levels to prevent suicide and suicide attempts. But can more be done? Yes, according to experts.

Researchers are investigating factors that contribute to suicide at the individual level, as well as environmental and societal pressures that may increase risk. New predictive tools show promise in identifying individuals at high risk, and ongoing programs offer hope for early and ongoing interventions. Successful preventive strategies are multimodal, emphasizing the need for trained primary care and mental health professionals to work together to identify and support individuals at risk at every age and in all settings.

 

‘Radical Change’ Needed

The medical community’s approach to suicide prevention is all wrong, according to Igor Galynker, MD, PhD, clinical professor of psychiatry and director of the Mount Sinai Suicide Prevention Research Lab in New York City. 

Galynker is collaborating with colleagues in various parts of the world, including Europe, to validate the use of suicide crisis syndrome (SCS) as a diagnosis to help imminent suicide risk evaluation and treatment.

SCS is a negative cognitive-affective state associated with imminent suicidal behavior in those who are already at high risk for suicide. Galynker and his colleagues want to see SCS recognized and accepted as a suicide-specific diagnosis in the Diagnostic and Statistical Manual of Mental Disorders and the World Health Organization’s International Classification of Diseases. 

Currently, he explained to this news organization, clinicians depend on a person at risk for suicide telling them that this is what they are feeling. This is “absurd,” he said, because people in this situation are in acute pain and distress and cannot answer accurately.

“It is the most lethal psychiatric condition, because people die from it ... yet we rely on people at the worst moment of their lives to tell us accurately when and how they are going to kill themselves. We don’t ask people with serious mental illness to diagnose their own mental illness and rely on that diagnosis.”

Data show that most people who attempt or die by suicide deny suicidal thoughts when assessed by healthcare providers using current questionnaires and scales. Thus, there needs to be “a radical change” in how patients at acute risk are assessed and treated to help “prevent suicides and avoid lost opportunities to intervene,” he said.

Galynker explained that SCS is the final and most acute stage of the “ narrative crisis model” of suicide, which reflects the progression of suicidal risk from chronic risk factors to imminent suicidal risk. “The narrative crisis model has four distinct and successive stages, with specific guidance and applicable interventions that enable patients to receive a stage-specific treatment.”

“Suicide crisis syndrome is a very treatable syndrome that rapidly resolves” with appropriate interventions, he said. “Once it is treated, the patient can engage with psychotherapy and other treatments.”

Galynker said he and his colleagues have had encouraging results with their studies so far on the subjective and objective views of clinicians using the risk assessment tools they are developing to assess suicidal ideation. Further studies are ongoing. 

 

Improving Prediction

There is definitely room for improvement in current approaches to suicide prevention, said Raffaella Calati, PhD, assistant professor of clinical psychology at the University of Milano-Bicocca, Italy, who has had research collaborations with Galynker.

Calati advocates for a more integrated approach across disciplines, institutions, and the community to provide an effective support network for those at risk. 

Accurately predicting suicide risk is challenging, she told this news organization. She and colleagues are working to develop more precise predictive tools for identifying individuals at risk, often by leveraging artificial intelligence and data analytics. They have designed and implemented app-based interventions for psychiatric patients at risk for suicide and university students with psychological distress. The interventions are personalized and based on multiple approaches, such as cognitive-behavioral therapy (CBT) and third-wave CBT. 

The results of current studies are preliminary, she acknowledged, “but even if apps are extremely complex, our projects received high interest from participants and the scientific community,” she said. The aim now is to integrate these tools into healthcare systems so that monitoring high-risk patients becomes part of regular care. 

Another area of focus is the identification of specific subtypes of individuals at risk for suicide, particularly by examining factors such as pain, dissociation, and interoception — the ability to sense and interpret internal signals from the body. 

“By understanding how these experiences intersect and contribute to suicide risk, I aim to identify distinct profiles within at-risk populations, which could ultimately enable more tailored and effective prevention efforts,” she said.

Her work also involves meta-research to build large, comprehensive datasets that increase statistical power for exploring suicide risk factors, such as physical health conditions and symptoms associated with borderline personality disorder. By creating these datasets, she aims to “improve understanding of how various factors contribute to suicide risk, ultimately supporting more effective prevention strategies.”

 

Country-Level Efforts

Preventive work is underway in other countries as well. In Nordic countries such as Denmark, Finland, and Sweden, large-scale national registries that track people’s medical histories, prescriptions, and demographic information are being used to develop predictive algorithms that identify those at high risk for suicide. The predictions are based on known risk factors like previous mental health diagnoses, substance abuse, and social determinants of health.

A recent Norwegian study found that a novel assessment tool used at admission to an acute inpatient unit was a powerful predictor of suicide within 3 years post-discharge.

Researchers in the Netherlands have also recently co-designed a digital integrated suicide prevention program, which has led to a significant reduction in suicide mortality. 

SUPREMOCOL (suicide prevention by monitoring and collaborative care) was implemented in Noord-Brabant, a province in the Netherlands that historically had high suicide rates. It combines technology and personal care, allowing healthcare providers to track a person’s mental health, including by phone calls, text messages, and mobile apps that help people express their feelings and report any changes in their mental state. By staying connected, the program aims to identify warning signs early and provide timely interventions.

The results from the 5-year project showed that rates dropped by 21.5%, from 14.4 per 100,000 to 11.8 per 100,000, and remained low, with a rate of 11.3 per 100,000 by 2021.

Finland used to have one of the highest suicide rates in the world. Now it is implementing its suicide prevention program for 2020-2030, with 36 proposed measures to prevent suicide mortality. 

The program includes measures such as increasing public awareness, early intervention, supporting at-risk groups, developing new treatment options, and enhancing research efforts. Earlier successful interventions included limiting access to firearms and poison, and increasing use of antidepressants and other targeted interventions.

“A key is to ensure that the individuals at risk of suicide have access to adequate, timely, and evidence-based care,” said Timo Partonen, MD, research professor at the Finnish Institute for Health and Welfare and associate professor of psychiatry at the University of Helsinki.

“Emergency and frontline professionals, as well as general practitioners and occupational health physicians, have a key role in identifying people at risk of suicide,” he noted. “High-quality competencies will be developed for healthcare professionals, including access to evidence-based suicide prevention models for addressing and assessing suicide risk.” 

 

Global Strategies

Policymakers across Europe are increasingly recognizing the importance of enhanced public health approaches to suicide prevention. 

The recently adopted EU Action Plan on Mental Health emphasizes the need for comprehensive suicide prevention strategies across Europe, including the promotion of mental health literacy and the provision of accessible mental health services.

The plan was informed by initiatives such as the European Alliance Against Depression (EAAD)-Best project, which ran from 2021 until March 2024. The collaborative project brought together researchers, healthcare providers, and community organizations to improve care for patients with depression and to prevent suicidal behavior in Europe. 

The multimodal approach included community engagement and training for healthcare professionals, as well as promoting the international uptake of the iFightDepression tool, an internet-based self-management approach for patients with depression. It has shown promise in reducing suicide rates in participating regions, including Europe, Australia, South America, and Africa.

“What we now know is that multiple interventions produce a synergic effect with a tendency to reduce suicidal behavior,” said EAAD founding member Ricardo Gusmão, MD, PhD, professor of public mental health at the University of Porto, Portugal. Current approaches to suicide prevention globally vary widely, with “many, fragmentary, atomized interventions, and we know that none of them, in isolation, produces spectacular results.” 

Gusmão explained that promising national suicide prevention strategies are based on multicomponent community interventions. On the clinical side, they encompass training primary health and specialized mental health professionals, and have a guaranteed chain of care and functioning pathways for access. They also involve educational programs in schools, universities, prisons, work settings, and geriatric care centers. Additionally, they have well-developed good standards for media communication and health marketing campaigns on well-being and mental health literacy.

Relevant and cohesive themes for successful strategies include the promotion of positive mental health, the identification and available treatments for depression and common mental disorders, and the management of suicidal crisis stigma. 

“We are now focusing on workplace settings and vulnerable groups such as youth, the elderly, unemployed, migrants and, of course, people affected by mental disorders,” he said. “Suicide prevention is like a web that must be weaved by long-lasting efforts and intersectoral collaboration.”

“Even one suicide is one too many,” Brendan Kelly, MD, PhD, professor of psychiatry, Trinity College Dublin, and author of The Modern Psychiatrist’s Guide to Contemporary Practice, told this news organization. “Nobody is born wanting to die by suicide. And every suicide is an individual tragedy, not a statistic. We need to work ever more intensively to reduce rates of suicide. All contributions to research and fresh thinking are welcome.”

Galynker, Calati, Partonen, and Kelly have disclosed no relevant financial relationships.  Gusmão has been involved in organizing Janssen-funded trainings for registrars on suicidal crisis management. 

 

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

A report published in July 2024 by the US Senate Special Committee on Aging is calling for a national coordinated response to what the authors claim may be an emerging hoarding disorder (HD) crisis.

While millions of US adults are estimated to have HD, it is the disorder’s prevalence and severity among older adults that sounded the alarm for the Committee Chair Sen. Bob Casey (D-PA).

HD affects roughly 2% of the overall population but up to 6% of all people older than 70 years, the report stated. Older adults made up about 16% of the US population in 2019. By 2060, that proportion is projected to soar to 25%.

The country’s aging population alone “could fuel a rise in hoarding in the coming decades,” the report authors noted.

These findings underscore the pressing need for a deeper understanding of HD, particularly as reports of its impact continue to rise. The Senate report also raises critical questions about the nature of HD: What is known about the condition? What evidence-based treatments are currently available, and are there national strategies that will prevent it from becoming a systemic crisis?

 

Why the Urgency?

An increase in anecdotal reports of HD in his home state prompted Casey, chair of the Senate Committee on Aging, to launch the investigation into the incidence and consequences of HD. Soon after the committee began its work, it became evident that the problem was not unique to communities in Pennsylvania. It was a nationwide issue.

“Communities throughout the United States are already grappling with HD,” the report noted.

HD is characterized by persistent difficulty discarding possessions, regardless of their monetary value. For individuals with HD, such items frequently hold meaningful reminders of past events and provide a sense of security. Difficulties with emotional regulation, executive functioning, and impulse control all contribute to the excessive buildup of clutter. Problems with attention, organization, and problem-solving are also common.

As individuals with HD age, physical limitations or disabilities may hinder their ability to discard clutter. As the accumulation increases, it can pose serious risks not only to their safety but also to public health.

Dozens of statements submitted to the Senate committee by those with HD, clinicians and social workers, first responders, social service organizations, state and federal agencies, and professional societies paint a concerning picture about the impact of hoarding on emergency and community services.

Data from the National Fire Incident Reporting System show the number of hoarding-related residential structural fires increased 26% between 2014 and 2022. Some 5242 residential fires connected to cluttered environments during that time resulted in 1367 fire service injuries, 1119 civilian injuries, and over $396 million in damages.

“For older adults, those consequences include health and safety risks, social isolation, eviction, and homelessness,” the report authors noted. “For communities, those consequences include public health concerns, increased risk of fire, and dangers to emergency responders.”

 

What Causes HD?

HD was once classified as a symptom of obsessive-compulsive personality disorder, with extreme causes meeting the diagnostic criteria for obsessive-compulsive disorder. That changed in 2010 when a working group recommended that HD be added to the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, as a stand-alone disorder. That recommendation was approved in 2012.

However, a decade later, much about HD’s etiology remains unknown.

Often beginning in early adolescence, HD is a chronic and progressive condition, with genetics and trauma playing a role in its onset and course, Sanjaya Saxena, MD, director of Clinical and Research Affairs at the International OCD Foundation, said in an interview.

Between 50% and 85% of people with HD symptoms have family members with similar behavior. HD is often comorbid with other psychiatric and medical disorders, which can complicate treatment.

Results of a 2022 study showed that, compared with healthy control individuals, people with HD had widespread abnormalities in the prefrontal white matter tract which connects cortical regions involved in executive functioning, including working memory, attention, reward processing, and decision-making.

Some research also suggests that dysregulation of serotonin transmission may contribute to compulsive behaviors and the difficulty in letting go of possessions.

“We do know that there are factors that contribute to worsening of hoarding symptoms, but that’s not the same thing as what really causes it. So unfortunately, it’s still very understudied, and we don’t have great knowledge of what causes it,” Saxena said.

 

What Treatments Are Available?

There are currently no Food and Drug Administration–approved medications to treat HD, although some research has shown antidepressants paroxetine and venlafaxine may have some benefit. Methylphenidate and atomoxetine are also under study for HD.

Nonpharmacological therapies have shown more promising results. Among the first was a specialized cognitive-behavioral therapy (CBT) program developed by Randy Frost, PhD, professor emeritus of psychology at Smith College in Northampton, Massachusetts, and Gail Steketee, PhD, dean emerita and professor emerita of social work at Boston University in Massachusetts.

First published in 2007 and the subject of many clinical trials and studies since, the 26-session program has served as a model for psychosocial treatments for HD. The evidence-based therapy addresses various symptoms, including impulse control. One module encourages participants to develop a set of questions to consider before acquiring new items, gradually helping them build resistance to the urge to accumulate more possessions, said Frost, whose early work on HD was cited by those who supported adding the condition to the DSM in 2012.

“There are several features that I think are important including exercises in resisting acquiring and processing information when making decisions about discarding,” Frost said in an interview.

A number of studies have demonstrated the efficacy of CBT for HD, including a 2015 meta-analysis coauthored by Frost. The research showed symptom severity decreased significantly following CBT, with the largest gains in difficulty discarding and moderate improvements in clutter and acquiring.

Responses were better among women and younger patients, and although symptoms improved, posttreatment scores remained closer to the clinical range, researchers noted. It’s possible that more intervention beyond what is usually included in clinical trials — such as more sessions or adding home decluttering visits — could improve treatment response, they added.

A workshop based on the specialized CBT program has expanded the reach of the treatment. The group therapy project, Buried in Treasures (BiT), was developed by Frost, Steketee, and David Tolin, PhD, founder and director of the Anxiety Disorders Center at the Institute of Living, Hartford, and an adjunct professor of psychiatry at Yale School of Medicine, New Haven, Connecticut. The workshop is designed as a facilitated treatment that can be delivered by clinicians or trained nonclinician facilitators.

A study published in May found that more than half the participants with HD responded to the treatment, and of those, 39% reported significant reductions in HD symptoms. BiT sessions were led by trained facilitators, and the study included in-home decluttering sessions, also led by trained volunteers. Researchers said adding the home intervention could increase engagement with the group therapy.

Another study of a modified version of BiT found a 32% decrease in HD symptoms after 15 weeks of treatment delivered via video teleconference.

“The BiT workshop has been expanding around the world and has the advantage of being relatively inexpensive,” Frost said. Another advantage is that it can be run by nonclinicians, which expands treatment options in areas where mental health professionals trained to treat HD are in short supply.

However, the workshop “is not perfect, and clients usually still have symptoms at the end of the workshop,” Frost noted.

“The point is that the BiT workshop is the first step in changing a lifestyle related to possessions,” he continued. “We do certainly need to train more people in how to treat hoarding, and we need to facilitate research to make our treatments more effective.”

 

What’s New in the Field?

One novel program currently under study combines CBT with a cognitive rehabilitation protocol. Called Cognitive Rehabilitation and Exposure/Sorting Therapy (CREST), the program has been shown to help older adults with HD who don’t respond to traditional CBT for HD.

The program, led by Catherine Ayers, PhD, professor of clinical psychiatry at University of California, San Diego, involves memory training and problem-solving combined with exposure therapy to help participants learn how to tolerate distress associated with discarding their possessions.

Early findings pointed to symptom improvement in older adults following 24 sessions with CREST. The program fared better than geriatric case management in a 2018 study — the first randomized controlled trial of a treatment for HD in older adults — and offered additional benefits compared with exposure therapy in a study published in February 2024.

Virtual reality is also helping people with HD. A program developed at Stanford University in California, allows people with HD to work with a therapist as they practice decluttering in a three-dimensional virtual environment created using photographs and videos of actual hoarded objects and cluttered rooms in patients’ homes.

In a small pilot study, nine people older than 55 years with HD attended 16 weeks of online facilitated therapy where they learned to better understand their attachment to those items. They practiced decluttering by selecting virtual items for recycling, donation, or trash. A virtual garbage truck even hauled away the items they had placed in the trash.

Participants were then asked to discard the actual items at home. Most participants reported a decrease in hoarding symptoms, which was confirmed following a home assessment by a clinician.

“When you pick up an object from a loved one, it still maybe has the scent of the loved one. It has these tactile cues, colors. But in the virtual world, you can take a little bit of a step back,” lead researchers Carolyn Rodriguez, MD, PhD, director of Stanford’s Hoarding Disorders Research Program, said in an interview.

“It’s a little ramp to help people practice these skills. And then what we find is that it actually translated really well. They were able to go home and actually do the real uncluttering,” Rodriguez added.

 

What Else Can Be Done?

While researchers like Rodriguez continue studies of new and existing treatments, the Senate report draws attention to other responses that could aid people with HD. Because of its significant impact on emergency responders, adult protective services, aging services, and housing providers, the report recommends a nationwide response to older adults with HD.

Currently, federal agencies in charge of mental and community health are not doing enough to address HD, the report’s authors noted.

The report demonstrates “the scope and severity of these challenges and offers a path forward for how we can help people, communities, and local governments contend with this condition,” Casey said.

Specifically, the document cites a lack of HD services and tracking by the Substance Abuse and Mental Health Services Administration, the Administration for Community Living, and the Centers for Disease Control and Prevention.

The committee recommended these agencies collaborate to improve HD data collection, which will be critical to managing a potential spike in cases as the population ages. The committee also suggested awareness and training campaigns to better educate clinicians, social service providers, court officials, and first responders about HD.

Further, the report’s authors called for the Department of Housing and Urban Development to provide guidance and technical assistance on HD for landlords and housing assistance programs and urged Congress to collaborate with the Centers for Medicare & Medicaid Services to expand coverage for hoarding treatments.

Finally, the committee encouraged policymakers to engage directly with individuals affected by HD and their families to better understand the impact of the disorder and inform policy development.

“I think the Senate report focuses on education, not just for therapists, but other stakeholders too,” Frost said. “There are lots of other professionals who have a stake in this process, housing specialists, elder service folks, health and human services. Awareness of this problem is something that’s important for them as well.”

Rodriguez characterized the report’s recommendations as “potentially lifesaving” for individuals with HD. She added that it represents the first step in an ongoing effort to address an impending public health crisis related to HD in older adults and its broader impact on communities.

A spokesperson with Casey’s office said it’s unclear whether any federal agencies have acted on the report recommendations since it was released in June. It’s also unknown whether the Senate Committee on Aging will pursue any additional work on HD when new committee leaders are appointed in 2025.

“Although some federal agencies have taken steps to address HD, those steps are frequently limited. Other relevant agencies have not addressed HD at all in recent years,” report authors wrote. “The federal government can, and should, do more to bolster the response to HD.”

Frost agreed.

“I think federal agencies can have a positive effect by promoting, supporting, and tracking local efforts in dealing with this problem,” he said.

With reporting from Eve Bender.

A version of this article appeared on Medscape.com.

A report published in July 2024 by the US Senate Special Committee on Aging is calling for a national coordinated response to what the authors claim may be an emerging hoarding disorder (HD) crisis.

While millions of US adults are estimated to have HD, it is the disorder’s prevalence and severity among older adults that sounded the alarm for the Committee Chair Sen. Bob Casey (D-PA).

HD affects roughly 2% of the overall population but up to 6% of all people older than 70 years, the report stated. Older adults made up about 16% of the US population in 2019. By 2060, that proportion is projected to soar to 25%.

The country’s aging population alone “could fuel a rise in hoarding in the coming decades,” the report authors noted.

These findings underscore the pressing need for a deeper understanding of HD, particularly as reports of its impact continue to rise. The Senate report also raises critical questions about the nature of HD: What is known about the condition? What evidence-based treatments are currently available, and are there national strategies that will prevent it from becoming a systemic crisis?

 

Why the Urgency?

An increase in anecdotal reports of HD in his home state prompted Casey, chair of the Senate Committee on Aging, to launch the investigation into the incidence and consequences of HD. Soon after the committee began its work, it became evident that the problem was not unique to communities in Pennsylvania. It was a nationwide issue.

“Communities throughout the United States are already grappling with HD,” the report noted.

HD is characterized by persistent difficulty discarding possessions, regardless of their monetary value. For individuals with HD, such items frequently hold meaningful reminders of past events and provide a sense of security. Difficulties with emotional regulation, executive functioning, and impulse control all contribute to the excessive buildup of clutter. Problems with attention, organization, and problem-solving are also common.

As individuals with HD age, physical limitations or disabilities may hinder their ability to discard clutter. As the accumulation increases, it can pose serious risks not only to their safety but also to public health.

Dozens of statements submitted to the Senate committee by those with HD, clinicians and social workers, first responders, social service organizations, state and federal agencies, and professional societies paint a concerning picture about the impact of hoarding on emergency and community services.

Data from the National Fire Incident Reporting System show the number of hoarding-related residential structural fires increased 26% between 2014 and 2022. Some 5242 residential fires connected to cluttered environments during that time resulted in 1367 fire service injuries, 1119 civilian injuries, and over $396 million in damages.

“For older adults, those consequences include health and safety risks, social isolation, eviction, and homelessness,” the report authors noted. “For communities, those consequences include public health concerns, increased risk of fire, and dangers to emergency responders.”

 

What Causes HD?

HD was once classified as a symptom of obsessive-compulsive personality disorder, with extreme causes meeting the diagnostic criteria for obsessive-compulsive disorder. That changed in 2010 when a working group recommended that HD be added to the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, as a stand-alone disorder. That recommendation was approved in 2012.

However, a decade later, much about HD’s etiology remains unknown.

Often beginning in early adolescence, HD is a chronic and progressive condition, with genetics and trauma playing a role in its onset and course, Sanjaya Saxena, MD, director of Clinical and Research Affairs at the International OCD Foundation, said in an interview.

Between 50% and 85% of people with HD symptoms have family members with similar behavior. HD is often comorbid with other psychiatric and medical disorders, which can complicate treatment.

Results of a 2022 study showed that, compared with healthy control individuals, people with HD had widespread abnormalities in the prefrontal white matter tract which connects cortical regions involved in executive functioning, including working memory, attention, reward processing, and decision-making.

Some research also suggests that dysregulation of serotonin transmission may contribute to compulsive behaviors and the difficulty in letting go of possessions.

“We do know that there are factors that contribute to worsening of hoarding symptoms, but that’s not the same thing as what really causes it. So unfortunately, it’s still very understudied, and we don’t have great knowledge of what causes it,” Saxena said.

 

What Treatments Are Available?

There are currently no Food and Drug Administration–approved medications to treat HD, although some research has shown antidepressants paroxetine and venlafaxine may have some benefit. Methylphenidate and atomoxetine are also under study for HD.

Nonpharmacological therapies have shown more promising results. Among the first was a specialized cognitive-behavioral therapy (CBT) program developed by Randy Frost, PhD, professor emeritus of psychology at Smith College in Northampton, Massachusetts, and Gail Steketee, PhD, dean emerita and professor emerita of social work at Boston University in Massachusetts.

First published in 2007 and the subject of many clinical trials and studies since, the 26-session program has served as a model for psychosocial treatments for HD. The evidence-based therapy addresses various symptoms, including impulse control. One module encourages participants to develop a set of questions to consider before acquiring new items, gradually helping them build resistance to the urge to accumulate more possessions, said Frost, whose early work on HD was cited by those who supported adding the condition to the DSM in 2012.

“There are several features that I think are important including exercises in resisting acquiring and processing information when making decisions about discarding,” Frost said in an interview.

A number of studies have demonstrated the efficacy of CBT for HD, including a 2015 meta-analysis coauthored by Frost. The research showed symptom severity decreased significantly following CBT, with the largest gains in difficulty discarding and moderate improvements in clutter and acquiring.

Responses were better among women and younger patients, and although symptoms improved, posttreatment scores remained closer to the clinical range, researchers noted. It’s possible that more intervention beyond what is usually included in clinical trials — such as more sessions or adding home decluttering visits — could improve treatment response, they added.

A workshop based on the specialized CBT program has expanded the reach of the treatment. The group therapy project, Buried in Treasures (BiT), was developed by Frost, Steketee, and David Tolin, PhD, founder and director of the Anxiety Disorders Center at the Institute of Living, Hartford, and an adjunct professor of psychiatry at Yale School of Medicine, New Haven, Connecticut. The workshop is designed as a facilitated treatment that can be delivered by clinicians or trained nonclinician facilitators.

A study published in May found that more than half the participants with HD responded to the treatment, and of those, 39% reported significant reductions in HD symptoms. BiT sessions were led by trained facilitators, and the study included in-home decluttering sessions, also led by trained volunteers. Researchers said adding the home intervention could increase engagement with the group therapy.

Another study of a modified version of BiT found a 32% decrease in HD symptoms after 15 weeks of treatment delivered via video teleconference.

“The BiT workshop has been expanding around the world and has the advantage of being relatively inexpensive,” Frost said. Another advantage is that it can be run by nonclinicians, which expands treatment options in areas where mental health professionals trained to treat HD are in short supply.

However, the workshop “is not perfect, and clients usually still have symptoms at the end of the workshop,” Frost noted.

“The point is that the BiT workshop is the first step in changing a lifestyle related to possessions,” he continued. “We do certainly need to train more people in how to treat hoarding, and we need to facilitate research to make our treatments more effective.”

 

What’s New in the Field?

One novel program currently under study combines CBT with a cognitive rehabilitation protocol. Called Cognitive Rehabilitation and Exposure/Sorting Therapy (CREST), the program has been shown to help older adults with HD who don’t respond to traditional CBT for HD.

The program, led by Catherine Ayers, PhD, professor of clinical psychiatry at University of California, San Diego, involves memory training and problem-solving combined with exposure therapy to help participants learn how to tolerate distress associated with discarding their possessions.

Early findings pointed to symptom improvement in older adults following 24 sessions with CREST. The program fared better than geriatric case management in a 2018 study — the first randomized controlled trial of a treatment for HD in older adults — and offered additional benefits compared with exposure therapy in a study published in February 2024.

Virtual reality is also helping people with HD. A program developed at Stanford University in California, allows people with HD to work with a therapist as they practice decluttering in a three-dimensional virtual environment created using photographs and videos of actual hoarded objects and cluttered rooms in patients’ homes.

In a small pilot study, nine people older than 55 years with HD attended 16 weeks of online facilitated therapy where they learned to better understand their attachment to those items. They practiced decluttering by selecting virtual items for recycling, donation, or trash. A virtual garbage truck even hauled away the items they had placed in the trash.

Participants were then asked to discard the actual items at home. Most participants reported a decrease in hoarding symptoms, which was confirmed following a home assessment by a clinician.

“When you pick up an object from a loved one, it still maybe has the scent of the loved one. It has these tactile cues, colors. But in the virtual world, you can take a little bit of a step back,” lead researchers Carolyn Rodriguez, MD, PhD, director of Stanford’s Hoarding Disorders Research Program, said in an interview.

“It’s a little ramp to help people practice these skills. And then what we find is that it actually translated really well. They were able to go home and actually do the real uncluttering,” Rodriguez added.

 

What Else Can Be Done?

While researchers like Rodriguez continue studies of new and existing treatments, the Senate report draws attention to other responses that could aid people with HD. Because of its significant impact on emergency responders, adult protective services, aging services, and housing providers, the report recommends a nationwide response to older adults with HD.

Currently, federal agencies in charge of mental and community health are not doing enough to address HD, the report’s authors noted.

The report demonstrates “the scope and severity of these challenges and offers a path forward for how we can help people, communities, and local governments contend with this condition,” Casey said.

Specifically, the document cites a lack of HD services and tracking by the Substance Abuse and Mental Health Services Administration, the Administration for Community Living, and the Centers for Disease Control and Prevention.

The committee recommended these agencies collaborate to improve HD data collection, which will be critical to managing a potential spike in cases as the population ages. The committee also suggested awareness and training campaigns to better educate clinicians, social service providers, court officials, and first responders about HD.

Further, the report’s authors called for the Department of Housing and Urban Development to provide guidance and technical assistance on HD for landlords and housing assistance programs and urged Congress to collaborate with the Centers for Medicare & Medicaid Services to expand coverage for hoarding treatments.

Finally, the committee encouraged policymakers to engage directly with individuals affected by HD and their families to better understand the impact of the disorder and inform policy development.

“I think the Senate report focuses on education, not just for therapists, but other stakeholders too,” Frost said. “There are lots of other professionals who have a stake in this process, housing specialists, elder service folks, health and human services. Awareness of this problem is something that’s important for them as well.”

Rodriguez characterized the report’s recommendations as “potentially lifesaving” for individuals with HD. She added that it represents the first step in an ongoing effort to address an impending public health crisis related to HD in older adults and its broader impact on communities.

A spokesperson with Casey’s office said it’s unclear whether any federal agencies have acted on the report recommendations since it was released in June. It’s also unknown whether the Senate Committee on Aging will pursue any additional work on HD when new committee leaders are appointed in 2025.

“Although some federal agencies have taken steps to address HD, those steps are frequently limited. Other relevant agencies have not addressed HD at all in recent years,” report authors wrote. “The federal government can, and should, do more to bolster the response to HD.”

Frost agreed.

“I think federal agencies can have a positive effect by promoting, supporting, and tracking local efforts in dealing with this problem,” he said.

With reporting from Eve Bender.

A version of this article appeared on Medscape.com.

A report published in July 2024 by the US Senate Special Committee on Aging is calling for a national coordinated response to what the authors claim may be an emerging hoarding disorder (HD) crisis.

While millions of US adults are estimated to have HD, it is the disorder’s prevalence and severity among older adults that sounded the alarm for the Committee Chair Sen. Bob Casey (D-PA).

HD affects roughly 2% of the overall population but up to 6% of all people older than 70 years, the report stated. Older adults made up about 16% of the US population in 2019. By 2060, that proportion is projected to soar to 25%.

The country’s aging population alone “could fuel a rise in hoarding in the coming decades,” the report authors noted.

These findings underscore the pressing need for a deeper understanding of HD, particularly as reports of its impact continue to rise. The Senate report also raises critical questions about the nature of HD: What is known about the condition? What evidence-based treatments are currently available, and are there national strategies that will prevent it from becoming a systemic crisis?

 

Why the Urgency?

An increase in anecdotal reports of HD in his home state prompted Casey, chair of the Senate Committee on Aging, to launch the investigation into the incidence and consequences of HD. Soon after the committee began its work, it became evident that the problem was not unique to communities in Pennsylvania. It was a nationwide issue.

“Communities throughout the United States are already grappling with HD,” the report noted.

HD is characterized by persistent difficulty discarding possessions, regardless of their monetary value. For individuals with HD, such items frequently hold meaningful reminders of past events and provide a sense of security. Difficulties with emotional regulation, executive functioning, and impulse control all contribute to the excessive buildup of clutter. Problems with attention, organization, and problem-solving are also common.

As individuals with HD age, physical limitations or disabilities may hinder their ability to discard clutter. As the accumulation increases, it can pose serious risks not only to their safety but also to public health.

Dozens of statements submitted to the Senate committee by those with HD, clinicians and social workers, first responders, social service organizations, state and federal agencies, and professional societies paint a concerning picture about the impact of hoarding on emergency and community services.

Data from the National Fire Incident Reporting System show the number of hoarding-related residential structural fires increased 26% between 2014 and 2022. Some 5242 residential fires connected to cluttered environments during that time resulted in 1367 fire service injuries, 1119 civilian injuries, and over $396 million in damages.

“For older adults, those consequences include health and safety risks, social isolation, eviction, and homelessness,” the report authors noted. “For communities, those consequences include public health concerns, increased risk of fire, and dangers to emergency responders.”

 

What Causes HD?

HD was once classified as a symptom of obsessive-compulsive personality disorder, with extreme causes meeting the diagnostic criteria for obsessive-compulsive disorder. That changed in 2010 when a working group recommended that HD be added to the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, as a stand-alone disorder. That recommendation was approved in 2012.

However, a decade later, much about HD’s etiology remains unknown.

Often beginning in early adolescence, HD is a chronic and progressive condition, with genetics and trauma playing a role in its onset and course, Sanjaya Saxena, MD, director of Clinical and Research Affairs at the International OCD Foundation, said in an interview.

Between 50% and 85% of people with HD symptoms have family members with similar behavior. HD is often comorbid with other psychiatric and medical disorders, which can complicate treatment.

Results of a 2022 study showed that, compared with healthy control individuals, people with HD had widespread abnormalities in the prefrontal white matter tract which connects cortical regions involved in executive functioning, including working memory, attention, reward processing, and decision-making.

Some research also suggests that dysregulation of serotonin transmission may contribute to compulsive behaviors and the difficulty in letting go of possessions.

“We do know that there are factors that contribute to worsening of hoarding symptoms, but that’s not the same thing as what really causes it. So unfortunately, it’s still very understudied, and we don’t have great knowledge of what causes it,” Saxena said.

 

What Treatments Are Available?

There are currently no Food and Drug Administration–approved medications to treat HD, although some research has shown antidepressants paroxetine and venlafaxine may have some benefit. Methylphenidate and atomoxetine are also under study for HD.

Nonpharmacological therapies have shown more promising results. Among the first was a specialized cognitive-behavioral therapy (CBT) program developed by Randy Frost, PhD, professor emeritus of psychology at Smith College in Northampton, Massachusetts, and Gail Steketee, PhD, dean emerita and professor emerita of social work at Boston University in Massachusetts.

First published in 2007 and the subject of many clinical trials and studies since, the 26-session program has served as a model for psychosocial treatments for HD. The evidence-based therapy addresses various symptoms, including impulse control. One module encourages participants to develop a set of questions to consider before acquiring new items, gradually helping them build resistance to the urge to accumulate more possessions, said Frost, whose early work on HD was cited by those who supported adding the condition to the DSM in 2012.

“There are several features that I think are important including exercises in resisting acquiring and processing information when making decisions about discarding,” Frost said in an interview.

A number of studies have demonstrated the efficacy of CBT for HD, including a 2015 meta-analysis coauthored by Frost. The research showed symptom severity decreased significantly following CBT, with the largest gains in difficulty discarding and moderate improvements in clutter and acquiring.

Responses were better among women and younger patients, and although symptoms improved, posttreatment scores remained closer to the clinical range, researchers noted. It’s possible that more intervention beyond what is usually included in clinical trials — such as more sessions or adding home decluttering visits — could improve treatment response, they added.

A workshop based on the specialized CBT program has expanded the reach of the treatment. The group therapy project, Buried in Treasures (BiT), was developed by Frost, Steketee, and David Tolin, PhD, founder and director of the Anxiety Disorders Center at the Institute of Living, Hartford, and an adjunct professor of psychiatry at Yale School of Medicine, New Haven, Connecticut. The workshop is designed as a facilitated treatment that can be delivered by clinicians or trained nonclinician facilitators.

A study published in May found that more than half the participants with HD responded to the treatment, and of those, 39% reported significant reductions in HD symptoms. BiT sessions were led by trained facilitators, and the study included in-home decluttering sessions, also led by trained volunteers. Researchers said adding the home intervention could increase engagement with the group therapy.

Another study of a modified version of BiT found a 32% decrease in HD symptoms after 15 weeks of treatment delivered via video teleconference.

“The BiT workshop has been expanding around the world and has the advantage of being relatively inexpensive,” Frost said. Another advantage is that it can be run by nonclinicians, which expands treatment options in areas where mental health professionals trained to treat HD are in short supply.

However, the workshop “is not perfect, and clients usually still have symptoms at the end of the workshop,” Frost noted.

“The point is that the BiT workshop is the first step in changing a lifestyle related to possessions,” he continued. “We do certainly need to train more people in how to treat hoarding, and we need to facilitate research to make our treatments more effective.”

 

What’s New in the Field?

One novel program currently under study combines CBT with a cognitive rehabilitation protocol. Called Cognitive Rehabilitation and Exposure/Sorting Therapy (CREST), the program has been shown to help older adults with HD who don’t respond to traditional CBT for HD.

The program, led by Catherine Ayers, PhD, professor of clinical psychiatry at University of California, San Diego, involves memory training and problem-solving combined with exposure therapy to help participants learn how to tolerate distress associated with discarding their possessions.

Early findings pointed to symptom improvement in older adults following 24 sessions with CREST. The program fared better than geriatric case management in a 2018 study — the first randomized controlled trial of a treatment for HD in older adults — and offered additional benefits compared with exposure therapy in a study published in February 2024.

Virtual reality is also helping people with HD. A program developed at Stanford University in California, allows people with HD to work with a therapist as they practice decluttering in a three-dimensional virtual environment created using photographs and videos of actual hoarded objects and cluttered rooms in patients’ homes.

In a small pilot study, nine people older than 55 years with HD attended 16 weeks of online facilitated therapy where they learned to better understand their attachment to those items. They practiced decluttering by selecting virtual items for recycling, donation, or trash. A virtual garbage truck even hauled away the items they had placed in the trash.

Participants were then asked to discard the actual items at home. Most participants reported a decrease in hoarding symptoms, which was confirmed following a home assessment by a clinician.

“When you pick up an object from a loved one, it still maybe has the scent of the loved one. It has these tactile cues, colors. But in the virtual world, you can take a little bit of a step back,” lead researchers Carolyn Rodriguez, MD, PhD, director of Stanford’s Hoarding Disorders Research Program, said in an interview.

“It’s a little ramp to help people practice these skills. And then what we find is that it actually translated really well. They were able to go home and actually do the real uncluttering,” Rodriguez added.

 

What Else Can Be Done?

While researchers like Rodriguez continue studies of new and existing treatments, the Senate report draws attention to other responses that could aid people with HD. Because of its significant impact on emergency responders, adult protective services, aging services, and housing providers, the report recommends a nationwide response to older adults with HD.

Currently, federal agencies in charge of mental and community health are not doing enough to address HD, the report’s authors noted.

The report demonstrates “the scope and severity of these challenges and offers a path forward for how we can help people, communities, and local governments contend with this condition,” Casey said.

Specifically, the document cites a lack of HD services and tracking by the Substance Abuse and Mental Health Services Administration, the Administration for Community Living, and the Centers for Disease Control and Prevention.

The committee recommended these agencies collaborate to improve HD data collection, which will be critical to managing a potential spike in cases as the population ages. The committee also suggested awareness and training campaigns to better educate clinicians, social service providers, court officials, and first responders about HD.

Further, the report’s authors called for the Department of Housing and Urban Development to provide guidance and technical assistance on HD for landlords and housing assistance programs and urged Congress to collaborate with the Centers for Medicare & Medicaid Services to expand coverage for hoarding treatments.

Finally, the committee encouraged policymakers to engage directly with individuals affected by HD and their families to better understand the impact of the disorder and inform policy development.

“I think the Senate report focuses on education, not just for therapists, but other stakeholders too,” Frost said. “There are lots of other professionals who have a stake in this process, housing specialists, elder service folks, health and human services. Awareness of this problem is something that’s important for them as well.”

Rodriguez characterized the report’s recommendations as “potentially lifesaving” for individuals with HD. She added that it represents the first step in an ongoing effort to address an impending public health crisis related to HD in older adults and its broader impact on communities.

A spokesperson with Casey’s office said it’s unclear whether any federal agencies have acted on the report recommendations since it was released in June. It’s also unknown whether the Senate Committee on Aging will pursue any additional work on HD when new committee leaders are appointed in 2025.

“Although some federal agencies have taken steps to address HD, those steps are frequently limited. Other relevant agencies have not addressed HD at all in recent years,” report authors wrote. “The federal government can, and should, do more to bolster the response to HD.”

Frost agreed.

“I think federal agencies can have a positive effect by promoting, supporting, and tracking local efforts in dealing with this problem,” he said.

With reporting from Eve Bender.

A version of this article appeared on Medscape.com.

TOPLINE:

US alcohol-related mortality rates increased from 10.7 to 21.6 per 100,000 between 1999 and 2020, with the largest rise of 3.8-fold observed in adults aged 25-34 years. Women experienced a 2.5-fold increase, while the Midwest region showed a similar rise in mortality rates.

METHODOLOGY:

• Analysis utilized the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research to examine alcohol-related mortality trends from 1999 to 2020.
• Researchers analyzed data from a total US population of 180,408,769 people aged 25 to 85+ years in 1999 and 226,635,013 people in 2020.
• International Classification of Diseases, Tenth Revision, codes were used to identify deaths with alcohol attribution, including mental and behavioral disorders, alcoholic organ damage, and alcohol-related poisoning.

TAKEAWAY:

• Overall mortality rates increased from 10.7 (95% CI, 10.6-10.8) per 100,000 in 1999 to 21.6 (95% CI, 21.4-21.8) per 100,000 in 2020, representing a significant twofold increase.
• Adults aged 55-64 years demonstrated both the steepest increase and highest absolute rates in both 1999 and 2020.
• American Indian and Alaska Native individuals experienced the steepest increase and highest absolute rates among all racial groups.
• The West region maintained the highest absolute rates in both 1999 and 2020, despite the Midwest showing the largest increase.

IN PRACTICE:

“Individuals who consume large amounts of alcohol tend to have the highest risks of total mortality as well as deaths from cardiovascular disease. Cardiovascular disease deaths are predominantly due to myocardial infarction and stroke. To mitigate these risks, health providers may wish to implement screening for alcohol use in primary care and other healthcare settings. By providing brief interventions and referrals to treatment, healthcare providers would be able to achieve the early identification of individuals at risk of alcohol-related harm and offer them the support and resources they need to reduce their alcohol consumption,” wrote the authors of the study.

SOURCE:

The study was led by Alexandra Matarazzo, BS, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton. It was published online in The American Journal of Medicine.

LIMITATIONS:

According to the authors, the cross-sectional nature of the data limits the study to descriptive analysis only, making it suitable for hypothesis generation but not hypothesis testing. While the validity and generalizability within the United States are secure because of the use of complete population data, potential bias and uncontrolled confounding may exist because of different population mixes between the two time points.

DISCLOSURES:

The authors reported no relevant conflicts of interest. One coauthor disclosed serving as an independent scientist in an advisory role to investigators and sponsors as Chair of Data Monitoring Committees for Amgen and UBC, to the Food and Drug Administration, and to Up to Date. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

US alcohol-related mortality rates increased from 10.7 to 21.6 per 100,000 between 1999 and 2020, with the largest rise of 3.8-fold observed in adults aged 25-34 years. Women experienced a 2.5-fold increase, while the Midwest region showed a similar rise in mortality rates.

METHODOLOGY:

• Analysis utilized the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research to examine alcohol-related mortality trends from 1999 to 2020.
• Researchers analyzed data from a total US population of 180,408,769 people aged 25 to 85+ years in 1999 and 226,635,013 people in 2020.
• International Classification of Diseases, Tenth Revision, codes were used to identify deaths with alcohol attribution, including mental and behavioral disorders, alcoholic organ damage, and alcohol-related poisoning.

TAKEAWAY:

• Overall mortality rates increased from 10.7 (95% CI, 10.6-10.8) per 100,000 in 1999 to 21.6 (95% CI, 21.4-21.8) per 100,000 in 2020, representing a significant twofold increase.
• Adults aged 55-64 years demonstrated both the steepest increase and highest absolute rates in both 1999 and 2020.
• American Indian and Alaska Native individuals experienced the steepest increase and highest absolute rates among all racial groups.
• The West region maintained the highest absolute rates in both 1999 and 2020, despite the Midwest showing the largest increase.

IN PRACTICE:

“Individuals who consume large amounts of alcohol tend to have the highest risks of total mortality as well as deaths from cardiovascular disease. Cardiovascular disease deaths are predominantly due to myocardial infarction and stroke. To mitigate these risks, health providers may wish to implement screening for alcohol use in primary care and other healthcare settings. By providing brief interventions and referrals to treatment, healthcare providers would be able to achieve the early identification of individuals at risk of alcohol-related harm and offer them the support and resources they need to reduce their alcohol consumption,” wrote the authors of the study.

SOURCE:

The study was led by Alexandra Matarazzo, BS, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton. It was published online in The American Journal of Medicine.

LIMITATIONS:

According to the authors, the cross-sectional nature of the data limits the study to descriptive analysis only, making it suitable for hypothesis generation but not hypothesis testing. While the validity and generalizability within the United States are secure because of the use of complete population data, potential bias and uncontrolled confounding may exist because of different population mixes between the two time points.

DISCLOSURES:

The authors reported no relevant conflicts of interest. One coauthor disclosed serving as an independent scientist in an advisory role to investigators and sponsors as Chair of Data Monitoring Committees for Amgen and UBC, to the Food and Drug Administration, and to Up to Date. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

US alcohol-related mortality rates increased from 10.7 to 21.6 per 100,000 between 1999 and 2020, with the largest rise of 3.8-fold observed in adults aged 25-34 years. Women experienced a 2.5-fold increase, while the Midwest region showed a similar rise in mortality rates.

METHODOLOGY:

• Analysis utilized the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research to examine alcohol-related mortality trends from 1999 to 2020.
• Researchers analyzed data from a total US population of 180,408,769 people aged 25 to 85+ years in 1999 and 226,635,013 people in 2020.
• International Classification of Diseases, Tenth Revision, codes were used to identify deaths with alcohol attribution, including mental and behavioral disorders, alcoholic organ damage, and alcohol-related poisoning.

TAKEAWAY:

• Overall mortality rates increased from 10.7 (95% CI, 10.6-10.8) per 100,000 in 1999 to 21.6 (95% CI, 21.4-21.8) per 100,000 in 2020, representing a significant twofold increase.
• Adults aged 55-64 years demonstrated both the steepest increase and highest absolute rates in both 1999 and 2020.
• American Indian and Alaska Native individuals experienced the steepest increase and highest absolute rates among all racial groups.
• The West region maintained the highest absolute rates in both 1999 and 2020, despite the Midwest showing the largest increase.

IN PRACTICE:

“Individuals who consume large amounts of alcohol tend to have the highest risks of total mortality as well as deaths from cardiovascular disease. Cardiovascular disease deaths are predominantly due to myocardial infarction and stroke. To mitigate these risks, health providers may wish to implement screening for alcohol use in primary care and other healthcare settings. By providing brief interventions and referrals to treatment, healthcare providers would be able to achieve the early identification of individuals at risk of alcohol-related harm and offer them the support and resources they need to reduce their alcohol consumption,” wrote the authors of the study.

SOURCE:

The study was led by Alexandra Matarazzo, BS, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton. It was published online in The American Journal of Medicine.

LIMITATIONS:

According to the authors, the cross-sectional nature of the data limits the study to descriptive analysis only, making it suitable for hypothesis generation but not hypothesis testing. While the validity and generalizability within the United States are secure because of the use of complete population data, potential bias and uncontrolled confounding may exist because of different population mixes between the two time points.

DISCLOSURES:

The authors reported no relevant conflicts of interest. One coauthor disclosed serving as an independent scientist in an advisory role to investigators and sponsors as Chair of Data Monitoring Committees for Amgen and UBC, to the Food and Drug Administration, and to Up to Date. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Could assessing the well-being of older patients create better treatment plans?

Researchers with the US Department of Veterans Affairs posit that doing so just might improve patient quality of life.

In an article in Medical Care, Dawne Vogt, PhD, and her colleagues described two surveys of well-being developed for use in clinical settings.

“Well-Being Signs” (WBS), a 1-minute screening, asks patients about how satisfied they are with the most important parts of their daily life, which could include time with family. It also asks how regularly involved they are in the activities and their level of functioning.

“Well-Being Brief” (WBB) is self-administered and asks more in-depth questions about finances, health, social relationships, and vocation. Clinicians can use the tool to make referrals to appropriate services like counseling or resources like senior centers.

“They’re not things that we’ve historically paid a lot of attention to, at least in the healthcare setting,” said Vogt, a research psychologist in the Women’s Health Sciences Division of the VA Boston Healthcare System in Massachusetts. “A growing body of research shows that they have really big implications for health.”

The two approaches stem from an increased awareness of the relationship between social determinants of health and outcomes. Both screenings can be implemented more effectively in a clinical setting than other measures because of their brevity and ease of use, she said.

Vogt shared that anecdotally, she finds patients are pleasantly surprised by the questionnaires “because they’re being seen in a way that they don’t always feel like they’re seen.”

Vogt said that the two well-being measurements are more nuanced than standard screenings for depression.

“A measure of depression tells you something much more narrow than a measure of well-being tells you,” she said, adding that identifying problem areas early can help prevent developing mental health disorders. For example, Vogt said that veterans with higher well-being are less likely to develop posttraumatic stress disorder when exposed to trauma.

The WBS has been validated, while the WBB questionnaire awaits final testing.

James Michail, MD, a family and geriatric physician with Providence Health & Services in Los Angeles, California, said he views the well-being screeners as launching points into discussing whether a treatment is enhancing or inhibiting a patient’s life.

“We have screenings for everything else but not for wellness, and the goal of care isn’t necessarily always treatment,” Michail said. “It’s taking the whole person into consideration. There’s a person behind the disease.”

Kendra Segura, MD, an obstetrician-gynecologist in Los Angeles, said she is open to using a well-being screener. Usually, building repertoire with a patient takes time, and sometimes only then can it allow for a more candid assessment of well-being.

“Over the course of several visits, that is when patients open up,” she said. “It’s when that starts to happen where they start to tell you about their well-being. It’s not an easy thing to establish.”

The authors of the article reported no relevant financial relationships.

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

Could assessing the well-being of older patients create better treatment plans?

Researchers with the US Department of Veterans Affairs posit that doing so just might improve patient quality of life.

In an article in Medical Care, Dawne Vogt, PhD, and her colleagues described two surveys of well-being developed for use in clinical settings.

“Well-Being Signs” (WBS), a 1-minute screening, asks patients about how satisfied they are with the most important parts of their daily life, which could include time with family. It also asks how regularly involved they are in the activities and their level of functioning.

“Well-Being Brief” (WBB) is self-administered and asks more in-depth questions about finances, health, social relationships, and vocation. Clinicians can use the tool to make referrals to appropriate services like counseling or resources like senior centers.

“They’re not things that we’ve historically paid a lot of attention to, at least in the healthcare setting,” said Vogt, a research psychologist in the Women’s Health Sciences Division of the VA Boston Healthcare System in Massachusetts. “A growing body of research shows that they have really big implications for health.”

The two approaches stem from an increased awareness of the relationship between social determinants of health and outcomes. Both screenings can be implemented more effectively in a clinical setting than other measures because of their brevity and ease of use, she said.

Vogt shared that anecdotally, she finds patients are pleasantly surprised by the questionnaires “because they’re being seen in a way that they don’t always feel like they’re seen.”

Vogt said that the two well-being measurements are more nuanced than standard screenings for depression.

“A measure of depression tells you something much more narrow than a measure of well-being tells you,” she said, adding that identifying problem areas early can help prevent developing mental health disorders. For example, Vogt said that veterans with higher well-being are less likely to develop posttraumatic stress disorder when exposed to trauma.

The WBS has been validated, while the WBB questionnaire awaits final testing.

James Michail, MD, a family and geriatric physician with Providence Health & Services in Los Angeles, California, said he views the well-being screeners as launching points into discussing whether a treatment is enhancing or inhibiting a patient’s life.

“We have screenings for everything else but not for wellness, and the goal of care isn’t necessarily always treatment,” Michail said. “It’s taking the whole person into consideration. There’s a person behind the disease.”

Kendra Segura, MD, an obstetrician-gynecologist in Los Angeles, said she is open to using a well-being screener. Usually, building repertoire with a patient takes time, and sometimes only then can it allow for a more candid assessment of well-being.

“Over the course of several visits, that is when patients open up,” she said. “It’s when that starts to happen where they start to tell you about their well-being. It’s not an easy thing to establish.”

The authors of the article reported no relevant financial relationships.

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

Could assessing the well-being of older patients create better treatment plans?

Researchers with the US Department of Veterans Affairs posit that doing so just might improve patient quality of life.

In an article in Medical Care, Dawne Vogt, PhD, and her colleagues described two surveys of well-being developed for use in clinical settings.

“Well-Being Signs” (WBS), a 1-minute screening, asks patients about how satisfied they are with the most important parts of their daily life, which could include time with family. It also asks how regularly involved they are in the activities and their level of functioning.

“Well-Being Brief” (WBB) is self-administered and asks more in-depth questions about finances, health, social relationships, and vocation. Clinicians can use the tool to make referrals to appropriate services like counseling or resources like senior centers.

“They’re not things that we’ve historically paid a lot of attention to, at least in the healthcare setting,” said Vogt, a research psychologist in the Women’s Health Sciences Division of the VA Boston Healthcare System in Massachusetts. “A growing body of research shows that they have really big implications for health.”

The two approaches stem from an increased awareness of the relationship between social determinants of health and outcomes. Both screenings can be implemented more effectively in a clinical setting than other measures because of their brevity and ease of use, she said.

Vogt shared that anecdotally, she finds patients are pleasantly surprised by the questionnaires “because they’re being seen in a way that they don’t always feel like they’re seen.”

Vogt said that the two well-being measurements are more nuanced than standard screenings for depression.

“A measure of depression tells you something much more narrow than a measure of well-being tells you,” she said, adding that identifying problem areas early can help prevent developing mental health disorders. For example, Vogt said that veterans with higher well-being are less likely to develop posttraumatic stress disorder when exposed to trauma.

The WBS has been validated, while the WBB questionnaire awaits final testing.

James Michail, MD, a family and geriatric physician with Providence Health & Services in Los Angeles, California, said he views the well-being screeners as launching points into discussing whether a treatment is enhancing or inhibiting a patient’s life.

“We have screenings for everything else but not for wellness, and the goal of care isn’t necessarily always treatment,” Michail said. “It’s taking the whole person into consideration. There’s a person behind the disease.”

Kendra Segura, MD, an obstetrician-gynecologist in Los Angeles, said she is open to using a well-being screener. Usually, building repertoire with a patient takes time, and sometimes only then can it allow for a more candid assessment of well-being.

“Over the course of several visits, that is when patients open up,” she said. “It’s when that starts to happen where they start to tell you about their well-being. It’s not an easy thing to establish.”

The authors of the article reported no relevant financial relationships.

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

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: This section explores why physicians often struggle to recognize burnout within themselves, partly due to stigma and a tendency to focus on productivity over well-being. Dr. Tyra Fainstad shares personal experiences of burnout symptoms, emphasizing the importance of awareness and self-reflection. Recognizing and addressing burnout early can help physicians find healthier coping strategies, avoid productivity traps, and seek support.

Key Takeaways:

• Many physicians struggle to identify burnout due to stigma and self-blame.
• Awareness of burnout symptoms is essential for early intervention and healthy coping.
• Seeking support can prevent burnout from worsening and improve quality of life.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad explores the ingrained culture in medicine that encourages self-criticism, with many physicians feeling that they must be hard on themselves to succeed. Dr Fainstad challenges this belief, advocating for self-compassion as a healthier alternative. The evolving medical field now includes physicians who prioritize well-being without sacrificing quality of care, underscoring the importance of self-kindness for sustainable practice.

Key Takeaways:

• Many physicians believe that self-criticism is necessary for success, a mindset rooted in medical culture.
• Practicing self-compassion can improve long-term resilience and prevent burnout.
• The changing landscape of healthcare supports a more balanced approach to physician well-being.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations. 

Lotte Dyrbye, has disclosed the following relevant financial relationships: Co-inventor of the Well-being Index and its derivatives, which Mayo Clinic has licensed. Dyrbye receives royalties.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.

Key Takeaways:

• Relying solely on external validation can deepen burnout and affect well-being.
• Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
• Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.

Key Takeaways:

• Relying solely on external validation can deepen burnout and affect well-being.
• Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
• Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

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

Summary and Key Highlights

Summary: Dr Tyra Fainstad shares her personal experience with burnout and the journey to recovery through coaching and self-compassion. She describes the pressures of seeking validation through external achievements, which ultimately led to a crisis in self-worth after medical training. Through coaching, she learned to cultivate a sense of internal fulfillment, reconnecting with her passion for medicine and achieving a healthier balance.

Key Takeaways:

• Relying solely on external validation can deepen burnout and affect well-being.
• Coaching empowers physicians to develop self-compassion and sustainable coping strategies.
• Shifting from external to internal validation strengthens long-term fulfillment and job satisfaction.

Our Editors Also Recommend: 

Medscape Physician Burnout & Depression Report 2024: ‘We Have Much Work to Do’

Medscape Hospitalist Burnout & Depression Report 2024: Seeking Progress, Balance 

Medscape Physician Lifestyle & Happiness Report 2024: The Ongoing Struggle for Balance 

A Transformative Rx for Burnout, Grief, and Illness: Dance 

 

Next Medscape Masters Event:

Stay at the forefront of obesity care. Register for exclusive insights and the latest treatment innovations.

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

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.