Essure implants arrived on the market in 2002 as permanent contraception for women older than age 45 years with children. They were recalled in 2017. Presented as an alternative to laparoscopic tubal ligation, this medical device resulted in rare side effects affecting thousands of women, most notably the nervous system, cardiovascular system, endocrine system, and musculoskeletal system.

Implant analysis protocol

A team from Lyon, France, studied the wear debris from these medical devices and their possible toxic health effects. They discovered that tin could be the cause of the implant’s toxicity. “My research focuses on a variety of medical devices, mostly joint replacements, and more specifically, hip replacements. I look at how these materials behave in humans and how the wear debris affects the body,” explained Ana Maria Trunfio-Sfarghiu, bioengineering expert and research associate with the French National Center for Scientific Research at the Lyon National Institute of Applied Sciences’ Contact and Structure Mechanics Laboratory.

“The problems with Essure implants started with a woman who had been using one for about 10 years and was experiencing side effects such as trouble concentrating and focusing, significant vaginal bleeding, extreme tiredness, hair loss, etc. She had the implant removed, and we retrieved it from her gynecologist and analyzed it alongside other implants,” said Ms. Trunfio-Sfarghiu.

“Together with the hospital, we set up an implant analysis protocol. We visited hospital teams to demonstrate how to prepare the biopsies, embedded in paraffin blocks, before sending them to us for analysis. We gave the same specimen preparation instructions for all subjects,” Ms. Trunfio-Sfarghiu explained.

After a year of clinical analysis, the Journal of Trace Elements in Medicine and Biology published an article about 18 cases.
 

Implant weld corrosion

The Essure implant measures a few centimeters long and resembles a small spring. Once it is released inside the fallopian tube, its goal is to create inflammation and block the tube. It triggers fibrosis, which prevents the sperm from reaching the egg. Premarketing tests had shown that the fibrosis surrounding the implant would keep it from moving. However, the pharmaceutical company hadn’t assessed the mechanical integrity of the spring weld, which was made of silver-tin.

During their analysis in collaboration with the Minapath laboratory, Ms. Trunfio-Sfarghiu’s team found that the weld had corroded and that tin particles had been released into the subjects’ bodies. “The study included about 40 women, and we found tin in all of them,” said Ms. Trunfio-Sfarghiu.

This weld corrosion has several possible consequences. “When the implant degrades, it can travel anywhere in the pelvis, like a needle moving through the body with no apparent destination. The surgeons who operate to remove it describe similar surgeries in military medicine when the patient has been hit by a bullet!”
 

Organotin toxicity

Although tin is not especially toxic for the body when ingested, it can bind to organic compounds if it passes through to the blood. “When tin binds to a carbon atom, it becomes organotin, a neurotoxin,” said Ms. Trunfio-Sfarghiu.

She said that this organotin can travel to the brain and trigger symptoms like those found in patients with Essure implants. “For the time being, there is insufficient data to assert that we found organotin in all subjects. Another more in-depth study would be needed to assess migration to the brain. For the past 2 years, we have tried to obtain academic funding to continue our research, so far without success. Academic and political authorities seem to be a bit scared of what we’ve found,” said Ms. Trunfio-Sfarghiu.

For her, “it’s how the implant was marketed that is problematic. The implant was designed to create local inflammation, inflammation in itself being difficult to control. Some women need to have their entire uterus and ovaries removed to resolve problems caused by the implant.”
 

Harm in the United States

Ms. Trunfio-Sfarghiu’s research has helped American victims obtain acknowledgment of their suffering in the United States. “But the harm caused to women by defective implants has yet to be acknowledged in France,” she added.

She explained that Essure was recalled in 2017 because sales were poor, not because it was deemed dangerous. Her conclusion? “No implant that creates inflammation should be authorized, especially if there is a surgical alternative, which there is here: tubal ligation.”

A version of this article appeared on Medscape.com. This article was translated from the Medscape French edition.

Essure implants arrived on the market in 2002 as permanent contraception for women older than age 45 years with children. They were recalled in 2017. Presented as an alternative to laparoscopic tubal ligation, this medical device resulted in rare side effects affecting thousands of women, most notably the nervous system, cardiovascular system, endocrine system, and musculoskeletal system.

Implant analysis protocol

A team from Lyon, France, studied the wear debris from these medical devices and their possible toxic health effects. They discovered that tin could be the cause of the implant’s toxicity. “My research focuses on a variety of medical devices, mostly joint replacements, and more specifically, hip replacements. I look at how these materials behave in humans and how the wear debris affects the body,” explained Ana Maria Trunfio-Sfarghiu, bioengineering expert and research associate with the French National Center for Scientific Research at the Lyon National Institute of Applied Sciences’ Contact and Structure Mechanics Laboratory.

“The problems with Essure implants started with a woman who had been using one for about 10 years and was experiencing side effects such as trouble concentrating and focusing, significant vaginal bleeding, extreme tiredness, hair loss, etc. She had the implant removed, and we retrieved it from her gynecologist and analyzed it alongside other implants,” said Ms. Trunfio-Sfarghiu.

“Together with the hospital, we set up an implant analysis protocol. We visited hospital teams to demonstrate how to prepare the biopsies, embedded in paraffin blocks, before sending them to us for analysis. We gave the same specimen preparation instructions for all subjects,” Ms. Trunfio-Sfarghiu explained.

After a year of clinical analysis, the Journal of Trace Elements in Medicine and Biology published an article about 18 cases.
 

Implant weld corrosion

The Essure implant measures a few centimeters long and resembles a small spring. Once it is released inside the fallopian tube, its goal is to create inflammation and block the tube. It triggers fibrosis, which prevents the sperm from reaching the egg. Premarketing tests had shown that the fibrosis surrounding the implant would keep it from moving. However, the pharmaceutical company hadn’t assessed the mechanical integrity of the spring weld, which was made of silver-tin.

During their analysis in collaboration with the Minapath laboratory, Ms. Trunfio-Sfarghiu’s team found that the weld had corroded and that tin particles had been released into the subjects’ bodies. “The study included about 40 women, and we found tin in all of them,” said Ms. Trunfio-Sfarghiu.

This weld corrosion has several possible consequences. “When the implant degrades, it can travel anywhere in the pelvis, like a needle moving through the body with no apparent destination. The surgeons who operate to remove it describe similar surgeries in military medicine when the patient has been hit by a bullet!”
 

Organotin toxicity

Although tin is not especially toxic for the body when ingested, it can bind to organic compounds if it passes through to the blood. “When tin binds to a carbon atom, it becomes organotin, a neurotoxin,” said Ms. Trunfio-Sfarghiu.

She said that this organotin can travel to the brain and trigger symptoms like those found in patients with Essure implants. “For the time being, there is insufficient data to assert that we found organotin in all subjects. Another more in-depth study would be needed to assess migration to the brain. For the past 2 years, we have tried to obtain academic funding to continue our research, so far without success. Academic and political authorities seem to be a bit scared of what we’ve found,” said Ms. Trunfio-Sfarghiu.

For her, “it’s how the implant was marketed that is problematic. The implant was designed to create local inflammation, inflammation in itself being difficult to control. Some women need to have their entire uterus and ovaries removed to resolve problems caused by the implant.”
 

Harm in the United States

Ms. Trunfio-Sfarghiu’s research has helped American victims obtain acknowledgment of their suffering in the United States. “But the harm caused to women by defective implants has yet to be acknowledged in France,” she added.

She explained that Essure was recalled in 2017 because sales were poor, not because it was deemed dangerous. Her conclusion? “No implant that creates inflammation should be authorized, especially if there is a surgical alternative, which there is here: tubal ligation.”

A version of this article appeared on Medscape.com. This article was translated from the Medscape French edition.

Essure implants arrived on the market in 2002 as permanent contraception for women older than age 45 years with children. They were recalled in 2017. Presented as an alternative to laparoscopic tubal ligation, this medical device resulted in rare side effects affecting thousands of women, most notably the nervous system, cardiovascular system, endocrine system, and musculoskeletal system.

Implant analysis protocol

A team from Lyon, France, studied the wear debris from these medical devices and their possible toxic health effects. They discovered that tin could be the cause of the implant’s toxicity. “My research focuses on a variety of medical devices, mostly joint replacements, and more specifically, hip replacements. I look at how these materials behave in humans and how the wear debris affects the body,” explained Ana Maria Trunfio-Sfarghiu, bioengineering expert and research associate with the French National Center for Scientific Research at the Lyon National Institute of Applied Sciences’ Contact and Structure Mechanics Laboratory.

“The problems with Essure implants started with a woman who had been using one for about 10 years and was experiencing side effects such as trouble concentrating and focusing, significant vaginal bleeding, extreme tiredness, hair loss, etc. She had the implant removed, and we retrieved it from her gynecologist and analyzed it alongside other implants,” said Ms. Trunfio-Sfarghiu.

“Together with the hospital, we set up an implant analysis protocol. We visited hospital teams to demonstrate how to prepare the biopsies, embedded in paraffin blocks, before sending them to us for analysis. We gave the same specimen preparation instructions for all subjects,” Ms. Trunfio-Sfarghiu explained.

After a year of clinical analysis, the Journal of Trace Elements in Medicine and Biology published an article about 18 cases.
 

Implant weld corrosion

The Essure implant measures a few centimeters long and resembles a small spring. Once it is released inside the fallopian tube, its goal is to create inflammation and block the tube. It triggers fibrosis, which prevents the sperm from reaching the egg. Premarketing tests had shown that the fibrosis surrounding the implant would keep it from moving. However, the pharmaceutical company hadn’t assessed the mechanical integrity of the spring weld, which was made of silver-tin.

During their analysis in collaboration with the Minapath laboratory, Ms. Trunfio-Sfarghiu’s team found that the weld had corroded and that tin particles had been released into the subjects’ bodies. “The study included about 40 women, and we found tin in all of them,” said Ms. Trunfio-Sfarghiu.

This weld corrosion has several possible consequences. “When the implant degrades, it can travel anywhere in the pelvis, like a needle moving through the body with no apparent destination. The surgeons who operate to remove it describe similar surgeries in military medicine when the patient has been hit by a bullet!”
 

Organotin toxicity

Although tin is not especially toxic for the body when ingested, it can bind to organic compounds if it passes through to the blood. “When tin binds to a carbon atom, it becomes organotin, a neurotoxin,” said Ms. Trunfio-Sfarghiu.

She said that this organotin can travel to the brain and trigger symptoms like those found in patients with Essure implants. “For the time being, there is insufficient data to assert that we found organotin in all subjects. Another more in-depth study would be needed to assess migration to the brain. For the past 2 years, we have tried to obtain academic funding to continue our research, so far without success. Academic and political authorities seem to be a bit scared of what we’ve found,” said Ms. Trunfio-Sfarghiu.

For her, “it’s how the implant was marketed that is problematic. The implant was designed to create local inflammation, inflammation in itself being difficult to control. Some women need to have their entire uterus and ovaries removed to resolve problems caused by the implant.”
 

Harm in the United States

Ms. Trunfio-Sfarghiu’s research has helped American victims obtain acknowledgment of their suffering in the United States. “But the harm caused to women by defective implants has yet to be acknowledged in France,” she added.

She explained that Essure was recalled in 2017 because sales were poor, not because it was deemed dangerous. Her conclusion? “No implant that creates inflammation should be authorized, especially if there is a surgical alternative, which there is here: tubal ligation.”

A version of this article appeared on Medscape.com. This article was translated from the Medscape French edition.

I had an early attraction to newspapers. As a child growing up in Jersey City, N.J., I delivered them door-to-door. I was editor-in-chief of my high school newspaper and worked as a copy boy and sports reporter on the daily Jersey Journal. At Princeton, I joined the University Press Club, working as a string reporter for the New York Herald Tribune, Philadelphia Inquirer, and Associated Press.

I thought I might become a journalist, but medicine was too strong a calling. During my GI elective as a senior medical resident at New York Hospital, I was able to work with some of the first commercial fiberoptic instruments, which presaged my academic career in endoscopic innovation. I was editor-in-chief of Gastrointestinal Endoscopy from 1988 to 1996, and have been the consulting editor for GI Endoscopy Clinics of North America since 1997.

As the first editor-in-chief of GI & Hepatology News, I had the opportunity to combine a background in peer review with my early newspaper experience. My vision for the new publication was to provide information curated and vetted by experts, in contrast to the torrent pouring down from the Internet that was (pertinent to our specialty) “indigestible.” I put in much effort selecting stories provided by Elsevier Global Medical News, especially in constructing the front page. AGA Institute provided strong support, allowing me to choose an editorial board covering all subspecialties. I wanted to highlight the excitement of researchers balanced by expert review and commentary. The digital version added search features, and I tried to promote the “browse factor” that would also encourage advertising, critical to the success of any newspaper. At the end of my term, I felt I had laid a strong foundation, and have been delighted to see the publication continue to thrive.
 

Charles Lightdale, MD, is professor of medicine at Columbia University Medical Center in New York. He disclosed having no conflicts of interest.

I had an early attraction to newspapers. As a child growing up in Jersey City, N.J., I delivered them door-to-door. I was editor-in-chief of my high school newspaper and worked as a copy boy and sports reporter on the daily Jersey Journal. At Princeton, I joined the University Press Club, working as a string reporter for the New York Herald Tribune, Philadelphia Inquirer, and Associated Press.

I thought I might become a journalist, but medicine was too strong a calling. During my GI elective as a senior medical resident at New York Hospital, I was able to work with some of the first commercial fiberoptic instruments, which presaged my academic career in endoscopic innovation. I was editor-in-chief of Gastrointestinal Endoscopy from 1988 to 1996, and have been the consulting editor for GI Endoscopy Clinics of North America since 1997.

As the first editor-in-chief of GI & Hepatology News, I had the opportunity to combine a background in peer review with my early newspaper experience. My vision for the new publication was to provide information curated and vetted by experts, in contrast to the torrent pouring down from the Internet that was (pertinent to our specialty) “indigestible.” I put in much effort selecting stories provided by Elsevier Global Medical News, especially in constructing the front page. AGA Institute provided strong support, allowing me to choose an editorial board covering all subspecialties. I wanted to highlight the excitement of researchers balanced by expert review and commentary. The digital version added search features, and I tried to promote the “browse factor” that would also encourage advertising, critical to the success of any newspaper. At the end of my term, I felt I had laid a strong foundation, and have been delighted to see the publication continue to thrive.
 

Charles Lightdale, MD, is professor of medicine at Columbia University Medical Center in New York. He disclosed having no conflicts of interest.

I had an early attraction to newspapers. As a child growing up in Jersey City, N.J., I delivered them door-to-door. I was editor-in-chief of my high school newspaper and worked as a copy boy and sports reporter on the daily Jersey Journal. At Princeton, I joined the University Press Club, working as a string reporter for the New York Herald Tribune, Philadelphia Inquirer, and Associated Press.

I thought I might become a journalist, but medicine was too strong a calling. During my GI elective as a senior medical resident at New York Hospital, I was able to work with some of the first commercial fiberoptic instruments, which presaged my academic career in endoscopic innovation. I was editor-in-chief of Gastrointestinal Endoscopy from 1988 to 1996, and have been the consulting editor for GI Endoscopy Clinics of North America since 1997.

As the first editor-in-chief of GI & Hepatology News, I had the opportunity to combine a background in peer review with my early newspaper experience. My vision for the new publication was to provide information curated and vetted by experts, in contrast to the torrent pouring down from the Internet that was (pertinent to our specialty) “indigestible.” I put in much effort selecting stories provided by Elsevier Global Medical News, especially in constructing the front page. AGA Institute provided strong support, allowing me to choose an editorial board covering all subspecialties. I wanted to highlight the excitement of researchers balanced by expert review and commentary. The digital version added search features, and I tried to promote the “browse factor” that would also encourage advertising, critical to the success of any newspaper. At the end of my term, I felt I had laid a strong foundation, and have been delighted to see the publication continue to thrive.
 

Charles Lightdale, MD, is professor of medicine at Columbia University Medical Center in New York. He disclosed having no conflicts of interest.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.

Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.

“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”

In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”

He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”

The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).

To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed ­–.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.

Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).

Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.

The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.

“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.

“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”

Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.

The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.

Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.

“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”

In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”

He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”

The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).

To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed ­–.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.

Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).

Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.

The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.

“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.

“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”

Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.

The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.

Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.

“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”

In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”

He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”

The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).

To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed ­–.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.

Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).

Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.

The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.

“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.

“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”

Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.

The Food and Drug Administration has cleared Abbot’s Freestyle Libre 3 system for use by people aged 4 years and older with diabetes.

The new system was cleared for use for both iOS- and Android-compatible mobile apps, enabling real-time glucose readings in contrast to the “intermittently scanned” capability of prior Libre versions. The Libre 3 allows for optional alarms and notifications of urgent low or high glucose levels, as well as remote monitoring by health care professionals or the patient’s family members and/or friends.

The FreeStyle Libre 3 was granted a CE Mark in Europe in October 2020.

Smaller, thinner, and better integration

According to Abbott, the Libre 3 is the first continuous glucose monitoring (CGM) system to show a mean absolute relative difference (MARD) of less than 8% compared with a gold-standard glucose measure. The average Libre 3 MARD is 7.9%, compared with 9.3% for the Libre 2. The Libre 3 is also the “smallest and thinnest” CGM, roughly the size of two stacked U.S. pennies, worn on the upper arm.

And, the company said, the Libre 3 has a Bluetooth integration of up to 33 feet, a range 50% further than other CGMs.   

This version follows the FreeStyle Libre 2, approved in June 2020, and its compatible iPhone app, approved in August 2021.

The Libre 3 will be priced the same as the Libre 2, at about one-third the cost of other CGM systems. However, it is not currently eligible for Medicare reimbursement. Medicaid eligibility may vary by state.

“I applaud Abbott for making their CGM system the most affordable and addressing disparities in care so patients living with diabetes can avoid complications and optimize their quality of life,” Eugene E. Wright Jr., MD, of Duke University, Durham, N.C., said in an Abbott statement.

“I have seen real-world evidence that diabetes technologies like CGMs have helped my patients safely achieve improved glycemic control,” he said.

The FreeStyle Libre 3 sensor will be available at participating pharmacies later this year.

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

The Food and Drug Administration has cleared Abbot’s Freestyle Libre 3 system for use by people aged 4 years and older with diabetes.

The new system was cleared for use for both iOS- and Android-compatible mobile apps, enabling real-time glucose readings in contrast to the “intermittently scanned” capability of prior Libre versions. The Libre 3 allows for optional alarms and notifications of urgent low or high glucose levels, as well as remote monitoring by health care professionals or the patient’s family members and/or friends.

The FreeStyle Libre 3 was granted a CE Mark in Europe in October 2020.

Smaller, thinner, and better integration

According to Abbott, the Libre 3 is the first continuous glucose monitoring (CGM) system to show a mean absolute relative difference (MARD) of less than 8% compared with a gold-standard glucose measure. The average Libre 3 MARD is 7.9%, compared with 9.3% for the Libre 2. The Libre 3 is also the “smallest and thinnest” CGM, roughly the size of two stacked U.S. pennies, worn on the upper arm.

And, the company said, the Libre 3 has a Bluetooth integration of up to 33 feet, a range 50% further than other CGMs.   

This version follows the FreeStyle Libre 2, approved in June 2020, and its compatible iPhone app, approved in August 2021.

The Libre 3 will be priced the same as the Libre 2, at about one-third the cost of other CGM systems. However, it is not currently eligible for Medicare reimbursement. Medicaid eligibility may vary by state.

“I applaud Abbott for making their CGM system the most affordable and addressing disparities in care so patients living with diabetes can avoid complications and optimize their quality of life,” Eugene E. Wright Jr., MD, of Duke University, Durham, N.C., said in an Abbott statement.

“I have seen real-world evidence that diabetes technologies like CGMs have helped my patients safely achieve improved glycemic control,” he said.

The FreeStyle Libre 3 sensor will be available at participating pharmacies later this year.

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

The Food and Drug Administration has cleared Abbot’s Freestyle Libre 3 system for use by people aged 4 years and older with diabetes.

The new system was cleared for use for both iOS- and Android-compatible mobile apps, enabling real-time glucose readings in contrast to the “intermittently scanned” capability of prior Libre versions. The Libre 3 allows for optional alarms and notifications of urgent low or high glucose levels, as well as remote monitoring by health care professionals or the patient’s family members and/or friends.

The FreeStyle Libre 3 was granted a CE Mark in Europe in October 2020.

Smaller, thinner, and better integration

According to Abbott, the Libre 3 is the first continuous glucose monitoring (CGM) system to show a mean absolute relative difference (MARD) of less than 8% compared with a gold-standard glucose measure. The average Libre 3 MARD is 7.9%, compared with 9.3% for the Libre 2. The Libre 3 is also the “smallest and thinnest” CGM, roughly the size of two stacked U.S. pennies, worn on the upper arm.

And, the company said, the Libre 3 has a Bluetooth integration of up to 33 feet, a range 50% further than other CGMs.   

This version follows the FreeStyle Libre 2, approved in June 2020, and its compatible iPhone app, approved in August 2021.

The Libre 3 will be priced the same as the Libre 2, at about one-third the cost of other CGM systems. However, it is not currently eligible for Medicare reimbursement. Medicaid eligibility may vary by state.

“I applaud Abbott for making their CGM system the most affordable and addressing disparities in care so patients living with diabetes can avoid complications and optimize their quality of life,” Eugene E. Wright Jr., MD, of Duke University, Durham, N.C., said in an Abbott statement.

“I have seen real-world evidence that diabetes technologies like CGMs have helped my patients safely achieve improved glycemic control,” he said.

The FreeStyle Libre 3 sensor will be available at participating pharmacies later this year.

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

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

Mr. J, age 23, presents to an outpatient mental health clinic for treatment of anxiety. He has no psychiatric history, is dressed neatly, and recently finished graduate school with a degree in accounting. Mr. J is reserved during the initial psychiatric evaluation and provides only basic facts about his developmental history.

Mr. J comes from a middle-class household with no history of trauma or substance use. He does not report any symptoms consistent with anxiety, but discloses a history of sexual preoccupations. Mr. J says that during adolescence he developed a predilection for observing others engage in sexual activity. In his late teens, he began following couples to their homes in the hope of witnessing sexual intimacy. In the rare instance that his voyeuristic fantasy comes to fruition, he masturbates and achieves sexual gratification he is incapable of experiencing otherwise. Mr. J notes that he has not yet been caught, but he expresses concern and embarrassment related to his actions. He concludes by noting that he seeks help because the frequency of this behavior has steadily increased.

How would you treat Mr. J? Where does the line exist between a normophilic sexual interest, fantasy or urge, and a paraphilia? Does Mr. J qualify as a sexually violent predator?

From The Rocky Horror Picture Show to Fifty Shades of Grey, sensationalized portrayals of sexual deviancy have long been present in popular culture. The continued popularity of serial killers years after their crimes seems in part related to the extreme sexual torture their victims often endure. However, a sexual offense does not always qualify as a paraphilic disorder.¹ In fact, many individuals with paraphilic disorders never engage in illegal activity. Additionally, experiencing sexually deviant thoughts alone does not qualify as a paraphilic disorder.¹

A thorough psychiatric evaluation should include a discussion of the patient’s sexual history, including the potential of sexual dysfunction and abnormal desires or behaviors. Most individuals with sexual dysfunction do not have a paraphilic disorder.² DSM-5 and ICD-11 classify sexual dysfunction and paraphilic disorders in different categories. However, previous editions grouped them together under sexual and gender identity disorders. Individuals with paraphilic disorders may not originally present to the outpatient setting for a paraphilic disorder, but instead may first seek treatment for a more common comorbid disorder, such as a mood disorder, personality disorder, or substance use disorder.³

Diagnostically speaking, if individuals do not experience distress or issues with functionality and lack legal charges (suggesting that they have not violated the rights of others), they are categorized as having an atypical sexual interest but do not necessarily meet the criteria for a disorder.⁴ This article provides an overview of paraphilic disorders as well as forensic considerations when examining individuals with sexually deviant behaviors.

Overview of paraphilic disorders

DSM-5 characterizes a paraphilic disorder as “recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects or nonconsenting partners for at least 6 months. The individual must have acted on the thought and/or it caused clinically significant distress or impairment in social, occupational, or other important areas of functioning.” DSM-5 outlines 9 categories of paraphilic disorders, which are described in Table 1.^4,5

Continue to: Paraphilic disorders are more common...

Paraphilic disorders are more common in men than in women; the 2 most prevalent are voyeuristic disorder and frotteuristic disorder.⁶ The incidence of paraphilias in the general outpatient setting varies by disorder. Approximately 45% of individuals with pedophilic disorder seek treatment, whereas only 1% of individuals with zoophilia seek treatment.⁶ The incidence of paraphilic acts also varies drastically; individuals with exhibitionistic disorder engaged in an average of 50 acts vs only 3 for individuals with sexual sadism.⁶ Not all individuals with paraphilic disorders commit crimes. Approximately 58% of sexual offenders meet the criteria for a paraphilic disorder, but antisocial personality disorder is a far more common diagnosis.⁷

Sexual psychopath statutes: Phase 1

In 1937, Michigan became the first state to enact sexual psychopath statutes, allowing for indeterminate sentencing and the civil commitment/treatment of sex offenders with repeated convictions. By the 1970s, more than 30 states had enacted similar statutes. It was not until 1967, in Specht v Patterson,⁸ that the United States Supreme Court unanimously ruled that the Fourteenth Amendment Due Process Clause was violated when Francis Eddie Specht faced life in prison following his conviction for indecent liberties under the Colorado Sex Offenders Act.

Specht was convicted in 1959 for indecent liberties after pleading guilty to enticing a child younger than age 16 into an office and engaging in sexual activities with them. At the time of Specht’s conviction, the crime of indecent liberties carried a punishment of 10 years. However, Specht was sentenced under the Sexual Offenders Act, which allowed for an indeterminate sentence of 1 day to life in prison. The Supreme Court noted that Specht was denied the right to be present with counsel, to confront the evidence against him, to cross-examine witnesses, and to offer his own evidence, which was a violation of his constitutionally guaranteed Fourteenth Amendment right to Procedural Due Process. The decision led most states to repeal early sexual psychopath statutes.⁸

Sexually violent predator laws: Phase 2

After early sexual psychopath statutes were repealed, many states pushed to update sex offender laws in response to the Earl Shriner case.⁹ In 1989, Shriner was released from prison after serving a 10-year sentence for sexually assaulting 2 teenage girls. At the time, he did not meet the criteria for civil commitment in the state of Washington. On the day he was released, Shriner cut off a young boy’s penis and left him to die. Washington subsequently became the first of many states to enact sexually violent predator (SVP) laws. Table 2¹⁰ shows states and districts that have SVP civil commitment laws.

A series of United States Supreme Court cases solidified current sexual offender civil commitment laws (Table 3^8,11-15).

Continue to: Allen v Illinois

Allen v Illinois (1986).¹¹ The Court ruled that forcing an individual to participate in a psychiatric evaluation prior to a sexually dangerous person’s commitment hearing did not violate the individual’s Fifth Amendment right against self-incrimination because the purpose of the evaluation was to provide treatment, not punishment.

Kansas v Hendricks (1997).¹² The Court upheld that the Kansas Sexually Violent Predator Act was constitutional and noted that the use of the broad term “mental abnormality” (in lieu of the more specific term “mental illness”) does not violate an individual’s Fourteenth Amendment right to substantive due process. Additionally, the Court opined that the constitutional ban on double jeopardy and ex post facto lawmaking does not apply because the procedures are civil, not criminal.

Kansas v Crane (2002).¹³ The Court upheld the Kansas Sexually Violent Predator Act, stating that mental illness and dangerousness are essential elements to meet the criteria for civil commitment. The Court added that proof of partial (not total) “volitional impairment” is all that is required to meet the threshold of sexual dangerousness.

McKune v Lile (2002).¹⁴ The Court ruled that a policy requiring participation in polygraph testing, which would lead to the disclosure of sexual crimes (even those that have not been prosecuted), does not violate an individual’s Fifth Amendment rights because it serves a vital penological purpose.

Adam Walsh Child Protection and Safety Act of 2006¹⁶; United States v Comstock (2010).¹⁵ This act and subsequent case reinforced the federal government’s right to civilly commit sexually dangerous persons approaching the end of their prison sentences.

Continue to: What is requiried for civil commitment?

What is required for civil commitment?

SVP laws require 4 conditions to be met for the civil commitment of sexual offenders (Table 4¹⁷). In criteria 1, “charges” is a key word, because this allows individuals found Not Guilty by Reason of Insanity or Incompetent to Stand Trial to be civilly committed. Criteria 2 defines “mental abnormality” as a “congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit criminal sexual acts in a degree constituting such person a menace to the health and safety of others.”¹⁸ This is a broad definition, and allows individuals with personality disorders to be civilly committed (although most sexual offenders are committed for having a paraphilic disorder). To determine risk, various actuarial instruments are used to assess for sexually violent recidivism, including (but not limited to) the Static-99R, Sexual Violence Risk-20, and the Sex Offender Risk Appraisal Guide.¹⁹

Although the percentages vary, sex offenders rarely are civilly committed following their criminal sentence. In California, approximately 1.5% of sex offenders are civilly committed.¹⁷ The standard of proof for civil commitment varies by state between “clear and convincing evidence” and “beyond a reasonable doubt.” As sex offenders approach the end of their sentence, sexually violent offenders are identified to the general population and referred for a psychiatric evaluation. If the individual meets the 4 criteria for commitment (Table 4¹⁷), their case is sent to the prosecuting attorney’s office. If accepted, the court holds a probable cause hearing, followed by a full trial.

Pornography and sex offenders

Pornography has long been considered a risk factor for sexual offending, and the role of pornography in influencing sexual behavior has drawn recent interest in research towards predicting future offenses. However, a 2019 systematic review by Mellor et al²⁰ on the relationship between pornography and sexual offending suggested that early exposure to pornography is not a risk factor for sexual offending, nor is the risk of offending increased shortly after pornography exposure. Additionally, pornography use did not predict recidivism in low-risk sexual offenders, but did in high-risk offenders.

The use of child pornography presents a set of new risk factors. Prohibited by federal and state law, child pornography is defined under Section 2256 of Title 18, United States Code, as any visual depiction of sexually explicit conduct involving a minor (someone <age 18). Visual depictions include photographs, videos, digital or computer-generated images indistinguishable from an actual minor, and images created to depict a minor. The law does not require an image of a child engaging in sexual activity for the image to be characterized as child pornography. Offenders are also commonly charged with the distribution of child pornography. A conviction of child pornography possession carries a 15- to 30-year sentence, and distribution carries a 5- to 20-year sentence.²¹ The individual must also file for the sex offender registry, which may restrict their employment and place of residency.

It is unclear what percentage of individuals charged with child pornography have a history of prior sexual offenses. Numerous studies suggest there is a low risk of online offenders without prior offenses becoming contact offenders. Characteristics of online-only offenders include being White, a single male, age 20 to 30, well-educated, and employed, and having antisocial traits and a history of sexual deviancy.²² Contact offenders tend to be married with easy access to children, unemployed, uneducated, and to have a history of mental illness or criminal offenses.²²

Continue to: Recidivism and treatment

Recidivism and treatment

The recidivism rate among sexual offenders averages 13.7% at 3- to 6-year follow-up,although rates vary by type of sexual offense.²³ Individuals who committed rape have the highest rate of recidivism, while those who engaged in incest have the lowest. Three key points about sexual offender recidivism are:

• it declines over time and with increased age.
• sexual offenders are more like to commit a nonsexual offense than a sexual offense.
• sexual offenders who have undergone treatment are 26.3% less likely to reoffend.²³

Although there is no standard of treatment, current interventions include external control, reduction of sexual drive, treatment of comorbid conditions, cognitive-behavioral therapy (CBT), and dynamic psychotherapy. External control relies on an outside entity that affects the individual’s behavior. For sexually deviant behaviors, simply making the act illegal or involving the law may inhibit many individuals from acting on a thought. Additional external control may include pharmacotherapy, which ranges from nonhormonal options such as selective serotonin reuptake inhibitors (SSRIs) to hormonal options. Therapy tends to focus on social skills training, sex education, cognitive restructuring, and identifying triggers, as well as victim empathy. The best indicators for successful treatment include an absence of comorbidities, increased age, and adult interpersonal relationships.²⁴

Treatment choice may be predicated on the severity of the paraphilia. Psychotherapy alone is recommended for individuals able to maintain functioning if it does not affect their conventional sexual activity. Common treatment for low-risk individuals is psychotherapy and an SSRI. As risk increases, so does treatment with pharmacologic agents. Beyond SSRIs, moderate offenders may be treated with an SSRI and a low-dose antiandrogen. This is escalated in high-risk violent offenders to long-acting gonadotropin-releasing hormone analogs and synthetic steroidal analogs.²⁵

An evolving class of disorders

With the evolution and accessibility of pornography, uncommon sexual practices have become more common, gaining notoriety and increased social acceptance. As a result, mental health professionals may be tasked with evaluating patients for possible paraphilic disorders. A common misconception is that individuals with sexually deviant thoughts, sexual offenders, and patients with paraphilic disorders are all the same. However, more commonly, sexual offenders do not have a paraphilic disorder. In the case of SVPs, outside of imprisonment, civil commitment remains a consideration for possible treatment. To meet the threshold of civil commitment, a sexual offender must have a “mental abnormality,” which is most commonly a paraphilic disorder. The treatment of paraphilic disorders remains a difficult task and includes a mixture of psychotherapy and medication options.

CASE CONTINUED

Mr. J begins weekly CBT to gain control of his voyeuristic fantasies without impacting his conventional sexual activity and desire. He responds well to treatment, and after 18 months, begins a typical sexual relationship with a woman. Although his voyeuristic thoughts remain, the urge to act on the thoughts decreases as Mr. J develops coping mechanisms. He does not require pharmacologic treatment.

Bottom Line

Individuals with paraphilic disorders are too often portrayed as sexual deviants or criminals. Psychiatrists must review each case with careful consideration of individual risk factors, such as the patient’s sexual history, to evaluate potential treatment options while determining if they pose a threat to the public.

Related Resources

• Sorrentino R, Abramowitz J. Minor-attracted persons: a neglected population. Current Psychiatry. 2021;20(7):21-27. doi:10.12788/cp.0149
• Berlin FS. Paraphilic disorders: a better understanding. Current Psychiatry. 2019;18(4):22-26,28.

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron

There is a need to connect mental and physical symptoms in the diagnosis and treatment of psychiatric disorders. Obviously, we are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. The science of defining the underlying mechanisms is lagging behind the clinical needs. However, in this article, we present a few hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. Our descriptions do not reflect the entire set of symptoms caused by these neurotransmitters; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypotheses we present.

In Part 1 (Current Psychiatry, May 2022), we argued that for depression, anxiety, psychosis, and bipolar disorder, development and approval of medications is currently based on descriptive diagnoses, with disregard to the various underlying causes of those conditions. Similar to how the many types of pneumonia are treated differently based on the specific infective agent, we suggested there are various types of depression or chronic pain based on the underlying neuro­transmitter pathology. Such an approach may be extrapolated to anxiety, psychosis, or bipolar disorder, although those conditions are outside the scope of this article. In Part 1, we described serotonin- and dopamine-associated mental and physical symptoms that suggest distinctly different types of depression or chronic pain, and we suggested specific ways of treating those described conditions. Part 2 reflects on pathology that is possibly connected to endorphin and norepinephrine dysfunction. Table 1 outlines medical and psychiatric symptoms that likely reflect endorphin excess^1-16 and deficiency,^1,16-24 and Table 2 lists symptoms that likely reflect norepinephrine excess^16,25-30and deficiency.^16,26,31-39 It is worth noting that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

Endorphin excess (Table 1^1-16)

Ms. R is a frustrated chronic pain patient who bitterly complains that despite having seen more than 20 physicians, she does not have an answer to what causes her “all over” pain and headache.^4,5,11 She does not believe that all her laboratory test are normal, and insists that “something is missing.” She aches all over but says she can actually tolerate more pain than others and experiences only a little discomfort during an electromyogram or dental interventions. Though Ms. R is not very susceptible to acute pain,^4,5,9,16 pain all over without an identifiable cause is part of her life.^4,5,11 She says that listening to music and social interactions help decrease her pain.^4,5,10 Ms. R states that opioid medications do not help her pain, though she has a history of opioid overuse and opioid-induced hyperalgesia.^6,11,16

Ms. R tends to overdo pleasureful activities to achieve satisfaction.² She says exercise is particularly satisfying, to the point that she experiences euphoria and a loss of time.⁹ She is angry that her neurologist suggested she see a psychiatrist. Her depression bothers her more than her anxiety.^2,5,7

Ms. R clearly has a self-image problem, alternating between high and low self-esteem. She has a low appetite^1,12,14-16 and sleeps excessively.^2,4,7,9,10 Her mother privately tells you that Ms. R has a history of childhood sexual abuse and lagged in life due to a lack of motivation. Ms. R used to self-mutilate “to feel normal.”¹² Her primary care physician chronically addresses Ms. R’s poorly explained cholestasis and pruritus⁸ as well as dysregulation of blood pressure and heart rate, both of which tend to be low.^12,13,16

Impression. Ms. R shows multiple symptoms associated with endorphin excess. A trial of an opioid antagonist may be reasonable. Dopamine blockade helps with endorphin suppression and also may be used for this patient. Using a low starting dose and a slow titration of such medications would be beneficial due to frequent intolerance issues, especially nausea. Gamma aminobutyric acid-ergic medications modulate the opioid system and may be considered. A serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine may help patients such as Ms. R to control mood and pain through norepinephrine’s influence on endorphins.

Endorphin deficiency (Table 1^1,16-24)

Mr. J complains of low back pain, diffuse body pain, depression, and moodiness.^19,20,24 He is sluggish and plagued by psychomotor retardation.²⁴ All his life, a heightened perception of pain has caused him problems,^19,20 but has not stopped him from engaging in self-mutilation.²⁴ His “unexplained” pain and general body aches seem to be associated with objectively verifiable pain generators (such as bruises and surgical procedures) but this pain is in excess of what would generally be expected. Mr. J describes his low back pain as mild degenerative disc disease and is eager to explain that his wife’s spine is more diseased, yet she has no back pain.

Continue to: Mr. J responds to treatment...

Mr. J responds to treatment with opioids^16,20 but comments that his mood, and not necessarily his pain, improves when he takes these medications.²⁰ He tends to overuse his pain medications, and had run into trouble with his previous pain management physician. Nitrous oxide is remarkably effective during dental procedures.¹⁹ Acupuncture helps to control his pain and mood.¹⁷ Exercise is also rewarding.¹⁸

Mr. J has difficulty achieving orgasm, a decreased sexual drive, and emotional sensitivity.²⁴ He is impulsive.^19,20,24 His baseline mood is low-grade; anxiety bothers him more than depression.^23,24 Mr. J is thin, has a poor appetite,^1,16 and sleeps poorly.²⁴ His primary care physician struggles to help Mr. J to control dysregulation of his heart rate, blood pressure,²¹ and urinary retention,^16,22 as well as episodes of hypoglycemia.^1,16 He reluctantly admits to abusing alcohol, but explains that it helps with his mood and pain better than his prescribed medications.^18,23

Impression. Mr. J exhibits multiple symptoms associated with endorphin deficiency. Short-term use of opioids is warranted, but he should avoid long-term opioid use, and he and his physician should work together to establish strict control of their intake. Buprenorphine would be the opioid of choice for such a patient. Psychiatric treatment, including for alcohol use disorder, should be a mandatory part of his treatment regimen. Behavioral therapy with a focus on finding healthy ways to achieve gratification would be effective. Alternative treatments such as acupuncture may be of value.

Norepinephrine excess (Table 2^16,25-30)

Mr. G comes to the office irritable and angry^28,30 because no one can help him with his intractable headaches.^16,25 He is pale, his breathing is noisy, and he licks his dry lips while sweating.^16,25 His wife is shy and seems to be afraid of her husband, who is easily irritated and edgy.^28,30 His heart rate and blood pressure are high; he has a history of palpitations and chest pain.^16,25 When unhappy, he gets pale, sweaty, tremulous, and nauseous.^16,25 He masks his anxiety with aggression and has impaired concentration, restless sleep, muscle tension, muscle cramps, and abdominal cramps.^27,28,30 Mr. G suffers from frequent nausea.^16,25 His neck is stiff and pupils are dilated; he clenches his teeth and uses a mouth guard for correction of temporomandibular joint disorder.^16,25 His sleep apnea is poorly controlled because he feels entrapped when he uses a continuous positive airway pressure machine.²⁹ He blames his wife for his premature ejaculation and says that she gives him goosebumps.²⁵ His hypervigilance and hyperarousal are torturous to his wife.^27,30 Despite his overall angry state, Mr. G is also constantly fearful.^28,30 He is almost never hungry, does not like crowds, hates your waiting area, and is vocal about his dislike of doctors being late “all the time.”^26,28,30

Comment. Norepinephrine and dopamine functions are connected through common neuronal and glial uptake mechanisms. This is a foundation of norepinephrine excess symptoms crossing over with symptoms of dopamine deficiency.

Continue to: Impression

Impression. Mr. G shows multiple symptoms associated with norepinephrine excess. It is important to avoid caffeine intake in patients with clinical signs of excessive norepinephrine. Beta-blockers and alpha-2 agonists work well in patients such as Mr. G. Benzodiazepines indirectly decrease norepinephrine activity, but need to be used carefully due to the potential for misuse and addiction. In particular, short-acting benzodiazepines such as alprazolam and lorazepam must be avoided due to the induction of CNS instability with rapidly changing medication blood levels. Chlordiazepoxide may be a good choice for a patient such as Mr. G because it has the fewest adverse effects and the lowest abuse potential compared with other benzodiazepines. Avoid SNRIs in such a patient. Using mood-stabilizing antipsychotic medications may be especially warranted in treating Mr. G’s depression and pain.

Norepinephrine deficiency (Table 2^16,26,31-39)

Two years ago, Ms. A was diagnosed with chronic fatigue³¹ and fibromyalgia. She also had been diagnosed with depression and attention-deficit/hyperactivity disorder (ADHD). She presents with concerns of “brain fog,” no energy, low sex drive, and daytime sleepiness.^33,35 Allodynia is widespread.^16,36,37 Ms. A suffers from bulimia; she eats once a day but is still overweight.²⁶ She has orthostatic hypotension in addition to baseline low blood pressure and bradycardia.^16,38,39 Her pupils are almost pinpoint, even when she does not take opioid medications.¹⁶ Her skin is dry and her hair is brittle; deep tendon reflexes are weakened, and her muscle tone is decreased.¹⁶ Ms. A’s constant low mood drives her to drink excessive amounts of caffeine, which she says “helps with daytime sleepiness but does not last”^32,33 and causes heart rhythm problems³⁸ and dyspepsia.¹⁶ She sees that her headaches and body pain are associated with her caffeine intake, but refuses to stop taking caffeine. Her low interest in life and general passivity have caused her many problems, though the problems themselves do not make her feel much.^31,32,39 She is rather indifferent to pleasurable activities, including sex.³¹ Her response to exciting experiences is blunted,³² but she is still frequently tearful.³⁴ Ms. A’s mood does not improve with selective serotonin reuptake inhibitors; she has tried many. She says that she would not come to see a physician, but “my mom told me to.” She resents that her family thinks she is lazy^31,32,39 and blames her ADHD for underperformance in life.^32,33 Ms. A has a family history of chronic pain and Alzheimer disease, and the longer she experiences pain, the worse her memory.³⁵

Comment. As mentioned earlier, because of the norepinephrine/dopamine relationship, symptoms of excess dopamine overlap with symptoms of norepinephrine deficiency.

Impression. Ms. A shows multiple symptoms associated with norepinephrine deficiency. The use of noradrenergic antidepressants (such as SNRIs and mirtazapine)²⁶ and stimulants may be warranted. Physical exercise, participating in social activities, massage, acupuncture, and family support may help with Ms. A’s pain as well as her depression, as might vasopressors.

In Part 3, we will address gamma aminobutyric acid and glutamate.

Bottom Line

Both high and low levels of endorphins and norepinephrine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (Part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Lorazepam • Ativan
Mirtazapine • Remeron

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon