Mixed Topics

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

[email protected]

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

[email protected]

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

[email protected]

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.

The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.

Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.

The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”

That course of events is not an outlier but everyday life for physicians trying to navigate insurers’ prior authorization rules before they can treat their patients. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.

Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.

“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”

When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”

Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.

“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”

Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”

The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “

Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”

For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”

In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”

Other survey findings also stand in direct contradiction of the 2018 consensus agreement:

A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.

Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.

Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.

Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.

“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”

In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.

In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.

If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.

Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”

The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said. 

Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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