On March 25, 2020, in Cambridge, United Kingdom, a 71-year-old man stabbed his 71-year-old wife before suffocating himself to death. The couple was reportedly anxious about the coronavirus disease 2019 (COVID-19) pandemic lockdown measures and were on the verge of running out of food and medicine.¹

One week later, in Chicago, Illinois, a 54-year-old man shot and killed his female partner, age 54, before killing himself. The couple was tested for COVID-19 2 days earlier and the man believed they had contracted the virus; however, the test results for both of them had come back negative.²

Intimate partner homicide-suicide is the most dramatic domestic abuse outcome.³ Homicide-suicide is defined as “homicide committed by a person who subsequently commits suicide within one week of the homicide. In most cases the subsequent suicide occurs within a 24-hour period.”⁴ Approximately one-quarter of all homicide-suicides are committed by persons age ≥55 years.^5,6 We believe that during the COVID-19 pandemic, the risk of homicide-suicide among older adults may be increased due to several factors, including:

• physical distancing and quarantine measures. Protocols established to slow the spread of the virus may be associated with increased rates of depression and anxiety⁷ and an increased risk of suicide among older adults⁸
• increased intimate partner violence⁹
• increased firearm ownership rates in the United States.¹⁰

In this article, we review studies that identified risk factors for homicide-suicide among older adults, discuss the impact the COVID-19 pandemic has had on these risks, and describe steps clinicians can take to intervene.

A review of the literature

To better characterize the perpetrators of older adult homicide-suicide, we conducted a literature search of relevant terms. We identified 9 original research publications that examined homicide-suicide in older adults.

Bourget et al¹¹ (2010) reviewed coroners’ charts of individuals killed by an older (age ≥65) spouse or family member from 1992 through 2007 in Quebec, Canada. They identified 19 cases of homicide-suicide, 17 (90%) of which were perpetrated by men. Perpetrators and victims were married (63%), in common-law relationships (16%), or separated/divorced (16%). A history of domestic violence was documented in 4 (21%) cases. The authors found that 13 of 15 perpetrators (87%) had “major depression” and 2 perpetrators had a psychotic disorder. Substance use at the time of the event was confirmed in 6 (32%) cases. Firearms and strangulation were the top methods used to carry out the homicide-suicide.¹¹

Cheung et al¹² (2016) conducted a review of coroners’ records of homicide-suicide cases among individuals age ≥65 in New Zealand from 2007 through 2012. In all 4 cases, the perpetrators were men, and their victims were predominantly female, live-in family members. Two cases involved men with a history of domestic violence who were undergoing significant changes in their home and social lives. Both men had a history suggestive of depression and used a firearm to carry out the homicide-suicide.¹²

Continue to: Cohen et al

Cohen et al¹³ (1998) conducted a review of coroners’ records from 1988 through 1994 in 2 regions in Florida. They found 48 intimate partner homicide-suicide cases among “old couples” (age ≥55). All were perpetrated by men. The authors identified sociocultural differences in risk factors between the 2 regions. In west-central Florida, perpetrators and victims were predominantly white and in a spousal relationship. Domestic violence was documented in <4% of cases. Approximately 55% of the couples were reported to be ill, and a substantial proportion were documented to be declining in health. One-quarter of the perpetrators and one-third of the victims had “pain and suffering.” More than one-third of perpetrators were reported to have “depression,” 15% were reported to have talked about suicide, and 4% had a history of a suicide attempt. Only 11% of perpetrators were described as abusing substances.

The authors noted several differences in cases in southeastern Florida. Approximately two-thirds of the couples were Hispanic, and 14% had a history of domestic violence. A minority of the couples were in a live-in relationship. Less than 15% of the perpetrators and victims were described as having a decline in health. Additionally, only 19% of perpetrators were reported to have “depression,” and none of the perpetrators had a documented history of attempted suicide or substance abuse. No information was provided regarding the methods used to carry out the homicide-suicide in the southeastern region.¹³ Financial stress was not a factor in either region.

Malphurs et al¹⁴ (2001) used the same database described in the Cohen et al¹³ study to compare 27 perpetrators of homicide-suicide to 36 age-matched suicide decedents in west central Florida. They found that homicide-suicide perpetrators were significantly less likely to have health problems and were 3 times more likely to be caregivers to their spouses. Approximately 52% of perpetrators had at least 1 documented psychiatric symptom (“depression” and/or substance abuse or other), but only 5% were seeking mental health services at the time of death.¹⁴

De Koning and Piette¹⁵ (2014) conducted a retrospective medicolegal chart review from 1935 to 2010 to identify homicide-suicide cases in West and East Flanders, Belgium. They found 19 cases of intimate partner homicide-suicide committed by offenders age ≥55 years. Ninety-five percent of the perpetrators were men who killed their female partners. In one-quarter of the cases, either the perpetrator or the victim had a health issue; 21% of the perpetrators were documented as having depression and 27% had alcohol intoxication at the time of death. A motive was documented in 14 out of 19 cases; “mercy killing” was determined as the motive in 6 (43%) cases and “amorous jealousy” in 5 cases (36%).¹⁵ Starting in the 1970s, firearms were the most prevalent method used to kill a partner.

Logan et al¹⁶ (2019) used data from the National Violent Death Reporting System between 2003 and 2015 to identify characteristics that differentiated male suicide decedents from male perpetrators of intimate partner homicide-suicide. They found that men age 50 to 64 years were 3 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide, and that men age ≥65 years were approximately 5 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide. The authors found that approximately 22% of all perpetrators had a documented history of physical domestic violence, and close to 17% had a prior interaction with the criminal justice system. Furthermore, one-third of perpetrators had relationship difficulties and were in the process of a breakup. Health issues were prevalent in 34% of the victims and 26% of the perpetrators. Perpetrator-caregiver burden was reported as a contributing factor for homicide-suicide in 16% of cases. In 27% of cases, multiple health-related contributing factors were mentioned.¹⁶

Continue to: Malphurs and Cohen

Malphurs and Cohen⁵ (2002) reviewed American newspapers from 1997 through 1999 and identified 673 homicide-suicide events, of which 152 (27%) were committed by individuals age ≥55 years. The victims and perpetrators (95% of which were men) were intimate partners in three-quarters of cases. In nearly one-third of cases, caregiving was a contributing factor for the homicide-suicide. A history of or a pending divorce was reported in nearly 14% of cases. Substance use history was rarely recorded. Firearms were used in 88% of the homicide-suicide cases.⁵

Malphurs and Cohen¹⁷ (2005) reviewed coroner records between 1998 and 1999 in Florida and compared 20 cases of intimate partner homicide-suicide involving perpetrators age ≥55 years with matched suicide decedents. They found that 60% of homicide-suicide perpetrators had documented health issues. The authors reported that a “recent change in health status” was more prevalent among perpetrators compared with decedents. Perpetrators were also more likely to be caregivers to their spouses. The authors found that 65% of perpetrators were reported to have a “depressed mood” and 15% of perpetrators had reportedly threatened suicide prior to the incident. However, none of the perpetrators tested positive for antidepressants as documented on post-mortem toxicology reports. Firearms were used in 100% of homicide-suicide cases.¹⁷

Salari³ (2007) reviewed multiple American media sources and published police reports between 1999 and 2005 to retrieve data about intimate partner homicide-suicide events in the United States. There were 225 events identified where the perpetrator and/or the victim were age ≥60 years. Ninety-six percent of the perpetrators were men and most homicide-suicide events were committed at the home. A history of domestic violence was reported in 14% of homicide-suicide cases. Thirteen percent of couples were separated or divorced. The perpetrator and/or victim had health issues in 124 (55%) events. Dementia was reported in 7.5% of cases, but overwhelmingly among the victims. Substance abuse was rarely mentioned as a contributing factor. In three-quarters of cases where a motive was described, the perpetrator was “suicidal”; however, a “suicide pact” was mentioned in only 4% of cases. Firearms were used in 87% of cases.³

Focus on common risk factors

The scarcity and heterogeneity of research regarding older adult homicide-suicide were major limitations to our review. Because most of the studies we identified had a small sample size and limited information regarding the mental health of victims and perpetrators, it would be an overreach to claim to have identified a typical profile of an older perpetrator of homicide-suicide. However, the literature has repeatedly identified several common characteristics of such perpetrators. They are significantly more likely to be men who use firearms to murder their intimate partners and then die by suicide in their home (Table^3,5,11-17). Health issues afflicting 1 or both individuals in the couple appear to be a contributing factor, particularly when the perpetrator is in a caregiving role. Relational discord, with or without a history of domestic violence, increases the risk of homicide-suicide. Finally, older perpetrators are highly likely to be depressed and have suicidal ideations.

How COVID-19 affects these risks

Although it is too early to determine if there is a causal relationship between the COVID-19 pandemic and an increase in homicide-suicide, the pandemic is likely to promote risk factors for these events, especially among older adults. Confinement measures put into place during the pandemic context have already been shown to increase rates of domestic violence¹⁸ and depression and anxiety among older individuals.⁷ Furthermore, contracting COVID-19 might be a risk factor for homicide-suicide in this vulnerable population. Caregivers might develop an “altruistic” motivation to kill their COVID-19–infected partner to reduce their partner’s suffering. Alternatively, caregivers’ motivation might be “egotistic,” aimed at reducing the overall suffering and burden on themselves, particularly if they contract COVID-19.¹⁹ This phenomenon might be preventable by acting on the modifiable risk factors.

Continue to: Late-life psychiatric disorders

Early recognition and effective treatment of late-life psychiatric disorders is crucial. Unfortunately, depression in geriatric patients is often underdiagnosed and undertreated.²⁰ Older adults have more frequent contact with their primary care physicians, and rarely consult mental health professionals.^21,22 Several models of integrated depression care within primary care settings have shown the positive impact of this collaborative approach in treating late-life depression and preventing suicide in older individuals.²³ Additionally, because alcohol abuse is also a risk factor for domestic violence and breaking the law in this population,^24,25 older adults should be screened for alcohol use disorders, and referred to treatment when necessary.

Take steps to keep patients safe

In the context of the COVID-19 pandemic, there are several steps clinicians need to keep in mind when interacting with older patients:

• Screen for depressive symptoms, suicidality, and alcohol and substance use disorders. Individuals who have tested positive for COVID-19 or who have been in contact with a carrier are a particularly vulnerable population.
• Screen for domestic violence and access to weapons at home.⁴ Any older adult who has a psychiatric disorder and/or suicide ideation should receive immediate intervention through a social worker that includes providing gun-risk education to other family members or contacting law-enforcement officials.²⁶
• Refer patients with a suspected psychiatric disorder to specialized mental health clinicians. Telemental health services can provide rapid access to subspecialists, allowing patients to be treated from their homes.²⁷ These services need to be promoted among older adults during this critical period and reimbursed by public and private insurance systems to ensure accessibility and affordability.²⁸
• Create psychiatric inpatient units specifically designed for suicidal and/or homicidal patients with COVID-19.

Additionally, informing the public about these major health issues is crucial. The media can raise awareness about domestic violence and depression among older adults; however, this should be done responsibly and with accuracy to prevent the spread of misinformation, confusion, fear, and panic.²⁹

Bottom Line

The mental health burden of the coronavirus disease 2019 pandemic has significantly impacted individuals who are older and most vulnerable. Reducing the incidence of homicide-suicide among older adults requires timely screening and interventions by primary care providers, mental health specialists, social workers, media, and governmental agencies.

Related Resources

• Saeed SA, Hebishi K. The psychiatric consequences of COVID-19: 8 studies. Current Psychiatry. 2020;19(11):22-24,28-30,32-35.
• Schwab-Reese LM, Murfree L, Coppola EC, et al. Homicidesuicide across the lifespan: a mixed methods examination of factors contributing to older adult perpetration. Aging Ment Health. 2020;20:1-9.

On March 25, 2020, in Cambridge, United Kingdom, a 71-year-old man stabbed his 71-year-old wife before suffocating himself to death. The couple was reportedly anxious about the coronavirus disease 2019 (COVID-19) pandemic lockdown measures and were on the verge of running out of food and medicine.¹

One week later, in Chicago, Illinois, a 54-year-old man shot and killed his female partner, age 54, before killing himself. The couple was tested for COVID-19 2 days earlier and the man believed they had contracted the virus; however, the test results for both of them had come back negative.²

Intimate partner homicide-suicide is the most dramatic domestic abuse outcome.³ Homicide-suicide is defined as “homicide committed by a person who subsequently commits suicide within one week of the homicide. In most cases the subsequent suicide occurs within a 24-hour period.”⁴ Approximately one-quarter of all homicide-suicides are committed by persons age ≥55 years.^5,6 We believe that during the COVID-19 pandemic, the risk of homicide-suicide among older adults may be increased due to several factors, including:

• physical distancing and quarantine measures. Protocols established to slow the spread of the virus may be associated with increased rates of depression and anxiety⁷ and an increased risk of suicide among older adults⁸
• increased intimate partner violence⁹
• increased firearm ownership rates in the United States.¹⁰

In this article, we review studies that identified risk factors for homicide-suicide among older adults, discuss the impact the COVID-19 pandemic has had on these risks, and describe steps clinicians can take to intervene.

A review of the literature

To better characterize the perpetrators of older adult homicide-suicide, we conducted a literature search of relevant terms. We identified 9 original research publications that examined homicide-suicide in older adults.

Bourget et al¹¹ (2010) reviewed coroners’ charts of individuals killed by an older (age ≥65) spouse or family member from 1992 through 2007 in Quebec, Canada. They identified 19 cases of homicide-suicide, 17 (90%) of which were perpetrated by men. Perpetrators and victims were married (63%), in common-law relationships (16%), or separated/divorced (16%). A history of domestic violence was documented in 4 (21%) cases. The authors found that 13 of 15 perpetrators (87%) had “major depression” and 2 perpetrators had a psychotic disorder. Substance use at the time of the event was confirmed in 6 (32%) cases. Firearms and strangulation were the top methods used to carry out the homicide-suicide.¹¹

Cheung et al¹² (2016) conducted a review of coroners’ records of homicide-suicide cases among individuals age ≥65 in New Zealand from 2007 through 2012. In all 4 cases, the perpetrators were men, and their victims were predominantly female, live-in family members. Two cases involved men with a history of domestic violence who were undergoing significant changes in their home and social lives. Both men had a history suggestive of depression and used a firearm to carry out the homicide-suicide.¹²

Continue to: Cohen et al

Cohen et al¹³ (1998) conducted a review of coroners’ records from 1988 through 1994 in 2 regions in Florida. They found 48 intimate partner homicide-suicide cases among “old couples” (age ≥55). All were perpetrated by men. The authors identified sociocultural differences in risk factors between the 2 regions. In west-central Florida, perpetrators and victims were predominantly white and in a spousal relationship. Domestic violence was documented in <4% of cases. Approximately 55% of the couples were reported to be ill, and a substantial proportion were documented to be declining in health. One-quarter of the perpetrators and one-third of the victims had “pain and suffering.” More than one-third of perpetrators were reported to have “depression,” 15% were reported to have talked about suicide, and 4% had a history of a suicide attempt. Only 11% of perpetrators were described as abusing substances.

The authors noted several differences in cases in southeastern Florida. Approximately two-thirds of the couples were Hispanic, and 14% had a history of domestic violence. A minority of the couples were in a live-in relationship. Less than 15% of the perpetrators and victims were described as having a decline in health. Additionally, only 19% of perpetrators were reported to have “depression,” and none of the perpetrators had a documented history of attempted suicide or substance abuse. No information was provided regarding the methods used to carry out the homicide-suicide in the southeastern region.¹³ Financial stress was not a factor in either region.

Malphurs et al¹⁴ (2001) used the same database described in the Cohen et al¹³ study to compare 27 perpetrators of homicide-suicide to 36 age-matched suicide decedents in west central Florida. They found that homicide-suicide perpetrators were significantly less likely to have health problems and were 3 times more likely to be caregivers to their spouses. Approximately 52% of perpetrators had at least 1 documented psychiatric symptom (“depression” and/or substance abuse or other), but only 5% were seeking mental health services at the time of death.¹⁴

De Koning and Piette¹⁵ (2014) conducted a retrospective medicolegal chart review from 1935 to 2010 to identify homicide-suicide cases in West and East Flanders, Belgium. They found 19 cases of intimate partner homicide-suicide committed by offenders age ≥55 years. Ninety-five percent of the perpetrators were men who killed their female partners. In one-quarter of the cases, either the perpetrator or the victim had a health issue; 21% of the perpetrators were documented as having depression and 27% had alcohol intoxication at the time of death. A motive was documented in 14 out of 19 cases; “mercy killing” was determined as the motive in 6 (43%) cases and “amorous jealousy” in 5 cases (36%).¹⁵ Starting in the 1970s, firearms were the most prevalent method used to kill a partner.

Logan et al¹⁶ (2019) used data from the National Violent Death Reporting System between 2003 and 2015 to identify characteristics that differentiated male suicide decedents from male perpetrators of intimate partner homicide-suicide. They found that men age 50 to 64 years were 3 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide, and that men age ≥65 years were approximately 5 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide. The authors found that approximately 22% of all perpetrators had a documented history of physical domestic violence, and close to 17% had a prior interaction with the criminal justice system. Furthermore, one-third of perpetrators had relationship difficulties and were in the process of a breakup. Health issues were prevalent in 34% of the victims and 26% of the perpetrators. Perpetrator-caregiver burden was reported as a contributing factor for homicide-suicide in 16% of cases. In 27% of cases, multiple health-related contributing factors were mentioned.¹⁶

Continue to: Malphurs and Cohen

Malphurs and Cohen⁵ (2002) reviewed American newspapers from 1997 through 1999 and identified 673 homicide-suicide events, of which 152 (27%) were committed by individuals age ≥55 years. The victims and perpetrators (95% of which were men) were intimate partners in three-quarters of cases. In nearly one-third of cases, caregiving was a contributing factor for the homicide-suicide. A history of or a pending divorce was reported in nearly 14% of cases. Substance use history was rarely recorded. Firearms were used in 88% of the homicide-suicide cases.⁵

Malphurs and Cohen¹⁷ (2005) reviewed coroner records between 1998 and 1999 in Florida and compared 20 cases of intimate partner homicide-suicide involving perpetrators age ≥55 years with matched suicide decedents. They found that 60% of homicide-suicide perpetrators had documented health issues. The authors reported that a “recent change in health status” was more prevalent among perpetrators compared with decedents. Perpetrators were also more likely to be caregivers to their spouses. The authors found that 65% of perpetrators were reported to have a “depressed mood” and 15% of perpetrators had reportedly threatened suicide prior to the incident. However, none of the perpetrators tested positive for antidepressants as documented on post-mortem toxicology reports. Firearms were used in 100% of homicide-suicide cases.¹⁷

Salari³ (2007) reviewed multiple American media sources and published police reports between 1999 and 2005 to retrieve data about intimate partner homicide-suicide events in the United States. There were 225 events identified where the perpetrator and/or the victim were age ≥60 years. Ninety-six percent of the perpetrators were men and most homicide-suicide events were committed at the home. A history of domestic violence was reported in 14% of homicide-suicide cases. Thirteen percent of couples were separated or divorced. The perpetrator and/or victim had health issues in 124 (55%) events. Dementia was reported in 7.5% of cases, but overwhelmingly among the victims. Substance abuse was rarely mentioned as a contributing factor. In three-quarters of cases where a motive was described, the perpetrator was “suicidal”; however, a “suicide pact” was mentioned in only 4% of cases. Firearms were used in 87% of cases.³

Focus on common risk factors

The scarcity and heterogeneity of research regarding older adult homicide-suicide were major limitations to our review. Because most of the studies we identified had a small sample size and limited information regarding the mental health of victims and perpetrators, it would be an overreach to claim to have identified a typical profile of an older perpetrator of homicide-suicide. However, the literature has repeatedly identified several common characteristics of such perpetrators. They are significantly more likely to be men who use firearms to murder their intimate partners and then die by suicide in their home (Table^3,5,11-17). Health issues afflicting 1 or both individuals in the couple appear to be a contributing factor, particularly when the perpetrator is in a caregiving role. Relational discord, with or without a history of domestic violence, increases the risk of homicide-suicide. Finally, older perpetrators are highly likely to be depressed and have suicidal ideations.

How COVID-19 affects these risks

Although it is too early to determine if there is a causal relationship between the COVID-19 pandemic and an increase in homicide-suicide, the pandemic is likely to promote risk factors for these events, especially among older adults. Confinement measures put into place during the pandemic context have already been shown to increase rates of domestic violence¹⁸ and depression and anxiety among older individuals.⁷ Furthermore, contracting COVID-19 might be a risk factor for homicide-suicide in this vulnerable population. Caregivers might develop an “altruistic” motivation to kill their COVID-19–infected partner to reduce their partner’s suffering. Alternatively, caregivers’ motivation might be “egotistic,” aimed at reducing the overall suffering and burden on themselves, particularly if they contract COVID-19.¹⁹ This phenomenon might be preventable by acting on the modifiable risk factors.

Continue to: Late-life psychiatric disorders

Early recognition and effective treatment of late-life psychiatric disorders is crucial. Unfortunately, depression in geriatric patients is often underdiagnosed and undertreated.²⁰ Older adults have more frequent contact with their primary care physicians, and rarely consult mental health professionals.^21,22 Several models of integrated depression care within primary care settings have shown the positive impact of this collaborative approach in treating late-life depression and preventing suicide in older individuals.²³ Additionally, because alcohol abuse is also a risk factor for domestic violence and breaking the law in this population,^24,25 older adults should be screened for alcohol use disorders, and referred to treatment when necessary.

Take steps to keep patients safe

In the context of the COVID-19 pandemic, there are several steps clinicians need to keep in mind when interacting with older patients:

• Screen for depressive symptoms, suicidality, and alcohol and substance use disorders. Individuals who have tested positive for COVID-19 or who have been in contact with a carrier are a particularly vulnerable population.
• Screen for domestic violence and access to weapons at home.⁴ Any older adult who has a psychiatric disorder and/or suicide ideation should receive immediate intervention through a social worker that includes providing gun-risk education to other family members or contacting law-enforcement officials.²⁶
• Refer patients with a suspected psychiatric disorder to specialized mental health clinicians. Telemental health services can provide rapid access to subspecialists, allowing patients to be treated from their homes.²⁷ These services need to be promoted among older adults during this critical period and reimbursed by public and private insurance systems to ensure accessibility and affordability.²⁸
• Create psychiatric inpatient units specifically designed for suicidal and/or homicidal patients with COVID-19.

Additionally, informing the public about these major health issues is crucial. The media can raise awareness about domestic violence and depression among older adults; however, this should be done responsibly and with accuracy to prevent the spread of misinformation, confusion, fear, and panic.²⁹

Bottom Line

The mental health burden of the coronavirus disease 2019 pandemic has significantly impacted individuals who are older and most vulnerable. Reducing the incidence of homicide-suicide among older adults requires timely screening and interventions by primary care providers, mental health specialists, social workers, media, and governmental agencies.

Related Resources

• Saeed SA, Hebishi K. The psychiatric consequences of COVID-19: 8 studies. Current Psychiatry. 2020;19(11):22-24,28-30,32-35.
• Schwab-Reese LM, Murfree L, Coppola EC, et al. Homicidesuicide across the lifespan: a mixed methods examination of factors contributing to older adult perpetration. Aging Ment Health. 2020;20:1-9.

On March 25, 2020, in Cambridge, United Kingdom, a 71-year-old man stabbed his 71-year-old wife before suffocating himself to death. The couple was reportedly anxious about the coronavirus disease 2019 (COVID-19) pandemic lockdown measures and were on the verge of running out of food and medicine.¹

One week later, in Chicago, Illinois, a 54-year-old man shot and killed his female partner, age 54, before killing himself. The couple was tested for COVID-19 2 days earlier and the man believed they had contracted the virus; however, the test results for both of them had come back negative.²

Intimate partner homicide-suicide is the most dramatic domestic abuse outcome.³ Homicide-suicide is defined as “homicide committed by a person who subsequently commits suicide within one week of the homicide. In most cases the subsequent suicide occurs within a 24-hour period.”⁴ Approximately one-quarter of all homicide-suicides are committed by persons age ≥55 years.^5,6 We believe that during the COVID-19 pandemic, the risk of homicide-suicide among older adults may be increased due to several factors, including:

• physical distancing and quarantine measures. Protocols established to slow the spread of the virus may be associated with increased rates of depression and anxiety⁷ and an increased risk of suicide among older adults⁸
• increased intimate partner violence⁹
• increased firearm ownership rates in the United States.¹⁰

In this article, we review studies that identified risk factors for homicide-suicide among older adults, discuss the impact the COVID-19 pandemic has had on these risks, and describe steps clinicians can take to intervene.

A review of the literature

To better characterize the perpetrators of older adult homicide-suicide, we conducted a literature search of relevant terms. We identified 9 original research publications that examined homicide-suicide in older adults.

Bourget et al¹¹ (2010) reviewed coroners’ charts of individuals killed by an older (age ≥65) spouse or family member from 1992 through 2007 in Quebec, Canada. They identified 19 cases of homicide-suicide, 17 (90%) of which were perpetrated by men. Perpetrators and victims were married (63%), in common-law relationships (16%), or separated/divorced (16%). A history of domestic violence was documented in 4 (21%) cases. The authors found that 13 of 15 perpetrators (87%) had “major depression” and 2 perpetrators had a psychotic disorder. Substance use at the time of the event was confirmed in 6 (32%) cases. Firearms and strangulation were the top methods used to carry out the homicide-suicide.¹¹

Cheung et al¹² (2016) conducted a review of coroners’ records of homicide-suicide cases among individuals age ≥65 in New Zealand from 2007 through 2012. In all 4 cases, the perpetrators were men, and their victims were predominantly female, live-in family members. Two cases involved men with a history of domestic violence who were undergoing significant changes in their home and social lives. Both men had a history suggestive of depression and used a firearm to carry out the homicide-suicide.¹²

Continue to: Cohen et al

Cohen et al¹³ (1998) conducted a review of coroners’ records from 1988 through 1994 in 2 regions in Florida. They found 48 intimate partner homicide-suicide cases among “old couples” (age ≥55). All were perpetrated by men. The authors identified sociocultural differences in risk factors between the 2 regions. In west-central Florida, perpetrators and victims were predominantly white and in a spousal relationship. Domestic violence was documented in <4% of cases. Approximately 55% of the couples were reported to be ill, and a substantial proportion were documented to be declining in health. One-quarter of the perpetrators and one-third of the victims had “pain and suffering.” More than one-third of perpetrators were reported to have “depression,” 15% were reported to have talked about suicide, and 4% had a history of a suicide attempt. Only 11% of perpetrators were described as abusing substances.

The authors noted several differences in cases in southeastern Florida. Approximately two-thirds of the couples were Hispanic, and 14% had a history of domestic violence. A minority of the couples were in a live-in relationship. Less than 15% of the perpetrators and victims were described as having a decline in health. Additionally, only 19% of perpetrators were reported to have “depression,” and none of the perpetrators had a documented history of attempted suicide or substance abuse. No information was provided regarding the methods used to carry out the homicide-suicide in the southeastern region.¹³ Financial stress was not a factor in either region.

Malphurs et al¹⁴ (2001) used the same database described in the Cohen et al¹³ study to compare 27 perpetrators of homicide-suicide to 36 age-matched suicide decedents in west central Florida. They found that homicide-suicide perpetrators were significantly less likely to have health problems and were 3 times more likely to be caregivers to their spouses. Approximately 52% of perpetrators had at least 1 documented psychiatric symptom (“depression” and/or substance abuse or other), but only 5% were seeking mental health services at the time of death.¹⁴

De Koning and Piette¹⁵ (2014) conducted a retrospective medicolegal chart review from 1935 to 2010 to identify homicide-suicide cases in West and East Flanders, Belgium. They found 19 cases of intimate partner homicide-suicide committed by offenders age ≥55 years. Ninety-five percent of the perpetrators were men who killed their female partners. In one-quarter of the cases, either the perpetrator or the victim had a health issue; 21% of the perpetrators were documented as having depression and 27% had alcohol intoxication at the time of death. A motive was documented in 14 out of 19 cases; “mercy killing” was determined as the motive in 6 (43%) cases and “amorous jealousy” in 5 cases (36%).¹⁵ Starting in the 1970s, firearms were the most prevalent method used to kill a partner.

Logan et al¹⁶ (2019) used data from the National Violent Death Reporting System between 2003 and 2015 to identify characteristics that differentiated male suicide decedents from male perpetrators of intimate partner homicide-suicide. They found that men age 50 to 64 years were 3 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide, and that men age ≥65 years were approximately 5 times more likely than men age 18 to 34 years to commit intimate partner homicide-suicide. The authors found that approximately 22% of all perpetrators had a documented history of physical domestic violence, and close to 17% had a prior interaction with the criminal justice system. Furthermore, one-third of perpetrators had relationship difficulties and were in the process of a breakup. Health issues were prevalent in 34% of the victims and 26% of the perpetrators. Perpetrator-caregiver burden was reported as a contributing factor for homicide-suicide in 16% of cases. In 27% of cases, multiple health-related contributing factors were mentioned.¹⁶

Continue to: Malphurs and Cohen

Malphurs and Cohen⁵ (2002) reviewed American newspapers from 1997 through 1999 and identified 673 homicide-suicide events, of which 152 (27%) were committed by individuals age ≥55 years. The victims and perpetrators (95% of which were men) were intimate partners in three-quarters of cases. In nearly one-third of cases, caregiving was a contributing factor for the homicide-suicide. A history of or a pending divorce was reported in nearly 14% of cases. Substance use history was rarely recorded. Firearms were used in 88% of the homicide-suicide cases.⁵

Malphurs and Cohen¹⁷ (2005) reviewed coroner records between 1998 and 1999 in Florida and compared 20 cases of intimate partner homicide-suicide involving perpetrators age ≥55 years with matched suicide decedents. They found that 60% of homicide-suicide perpetrators had documented health issues. The authors reported that a “recent change in health status” was more prevalent among perpetrators compared with decedents. Perpetrators were also more likely to be caregivers to their spouses. The authors found that 65% of perpetrators were reported to have a “depressed mood” and 15% of perpetrators had reportedly threatened suicide prior to the incident. However, none of the perpetrators tested positive for antidepressants as documented on post-mortem toxicology reports. Firearms were used in 100% of homicide-suicide cases.¹⁷

Salari³ (2007) reviewed multiple American media sources and published police reports between 1999 and 2005 to retrieve data about intimate partner homicide-suicide events in the United States. There were 225 events identified where the perpetrator and/or the victim were age ≥60 years. Ninety-six percent of the perpetrators were men and most homicide-suicide events were committed at the home. A history of domestic violence was reported in 14% of homicide-suicide cases. Thirteen percent of couples were separated or divorced. The perpetrator and/or victim had health issues in 124 (55%) events. Dementia was reported in 7.5% of cases, but overwhelmingly among the victims. Substance abuse was rarely mentioned as a contributing factor. In three-quarters of cases where a motive was described, the perpetrator was “suicidal”; however, a “suicide pact” was mentioned in only 4% of cases. Firearms were used in 87% of cases.³

Focus on common risk factors

The scarcity and heterogeneity of research regarding older adult homicide-suicide were major limitations to our review. Because most of the studies we identified had a small sample size and limited information regarding the mental health of victims and perpetrators, it would be an overreach to claim to have identified a typical profile of an older perpetrator of homicide-suicide. However, the literature has repeatedly identified several common characteristics of such perpetrators. They are significantly more likely to be men who use firearms to murder their intimate partners and then die by suicide in their home (Table^3,5,11-17). Health issues afflicting 1 or both individuals in the couple appear to be a contributing factor, particularly when the perpetrator is in a caregiving role. Relational discord, with or without a history of domestic violence, increases the risk of homicide-suicide. Finally, older perpetrators are highly likely to be depressed and have suicidal ideations.

How COVID-19 affects these risks

Although it is too early to determine if there is a causal relationship between the COVID-19 pandemic and an increase in homicide-suicide, the pandemic is likely to promote risk factors for these events, especially among older adults. Confinement measures put into place during the pandemic context have already been shown to increase rates of domestic violence¹⁸ and depression and anxiety among older individuals.⁷ Furthermore, contracting COVID-19 might be a risk factor for homicide-suicide in this vulnerable population. Caregivers might develop an “altruistic” motivation to kill their COVID-19–infected partner to reduce their partner’s suffering. Alternatively, caregivers’ motivation might be “egotistic,” aimed at reducing the overall suffering and burden on themselves, particularly if they contract COVID-19.¹⁹ This phenomenon might be preventable by acting on the modifiable risk factors.

Continue to: Late-life psychiatric disorders

Early recognition and effective treatment of late-life psychiatric disorders is crucial. Unfortunately, depression in geriatric patients is often underdiagnosed and undertreated.²⁰ Older adults have more frequent contact with their primary care physicians, and rarely consult mental health professionals.^21,22 Several models of integrated depression care within primary care settings have shown the positive impact of this collaborative approach in treating late-life depression and preventing suicide in older individuals.²³ Additionally, because alcohol abuse is also a risk factor for domestic violence and breaking the law in this population,^24,25 older adults should be screened for alcohol use disorders, and referred to treatment when necessary.

Take steps to keep patients safe

In the context of the COVID-19 pandemic, there are several steps clinicians need to keep in mind when interacting with older patients:

• Screen for depressive symptoms, suicidality, and alcohol and substance use disorders. Individuals who have tested positive for COVID-19 or who have been in contact with a carrier are a particularly vulnerable population.
• Screen for domestic violence and access to weapons at home.⁴ Any older adult who has a psychiatric disorder and/or suicide ideation should receive immediate intervention through a social worker that includes providing gun-risk education to other family members or contacting law-enforcement officials.²⁶
• Refer patients with a suspected psychiatric disorder to specialized mental health clinicians. Telemental health services can provide rapid access to subspecialists, allowing patients to be treated from their homes.²⁷ These services need to be promoted among older adults during this critical period and reimbursed by public and private insurance systems to ensure accessibility and affordability.²⁸
• Create psychiatric inpatient units specifically designed for suicidal and/or homicidal patients with COVID-19.

Additionally, informing the public about these major health issues is crucial. The media can raise awareness about domestic violence and depression among older adults; however, this should be done responsibly and with accuracy to prevent the spread of misinformation, confusion, fear, and panic.²⁹

Bottom Line

The mental health burden of the coronavirus disease 2019 pandemic has significantly impacted individuals who are older and most vulnerable. Reducing the incidence of homicide-suicide among older adults requires timely screening and interventions by primary care providers, mental health specialists, social workers, media, and governmental agencies.

Related Resources

• Saeed SA, Hebishi K. The psychiatric consequences of COVID-19: 8 studies. Current Psychiatry. 2020;19(11):22-24,28-30,32-35.
• Schwab-Reese LM, Murfree L, Coppola EC, et al. Homicidesuicide across the lifespan: a mixed methods examination of factors contributing to older adult perpetration. Aging Ment Health. 2020;20:1-9.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

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The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.