As the date for implementing ICD-10 gets closer, consulting firms send daily offers to help us adapt to the new diagnostic regime. As a service to the profession, Under My Skin will provide periodic updates to save you consulting fees.

In an earlier column, you learned about new codes like injury from burning water skis. We also covered codes for envenomation by Gila monsters, both unintentional and intentional. You should know that these are already available under ICD-9. No need to wait till next year to use them!

ICD-9-CM E905.0: Venomous snakes and lizards causing poisoning and toxic reactions. These include the following: cobra, copperhead snake, coral snake, fer-de-lance snake, Gila monster, krait, mamba, viper, and several others. Do NOT use this code for bites by nonvenomous snakes and lizards. (That may come back to bite you ... Sorry!)

Anyone who can define a fer-de-lance or a krait is gets extra credit (but no extra payment). If you can either identify a mamba, or dance it, good for you!

ICD-10 naturally amplifies this inadequate taxonomy:

• T63.111 – Toxic effect of venom of Gila monster, accidental (unintentional)

• T63.112 – Toxic effect of venom of Gila monster, intentional (self-harm)

• T63.113 – Toxic effect of venom of Gila monster, assault

• T63.114 – Toxic effect of venom of Gila monster, undetermined

Questions: For the new "assault" code, was the Gila monster the assailant or was its owner? Does "undetermined" mean you don’t really know how you got bitten (come on, was that really an accident – weren’t you petting the Gila kind of roughly?) or that you didn’t determine whether it actually was a Gila monster (because it ran away so fast that that it could have been a marmoset).

There are other ICD-9 codes you can already use (right now!) I recently got a 6-page EMR from a referring clinic (you get those, don’t you?) listing one of the patient’s 14 diagnoses as E968.2: Assault by striking by blunt or thrown object.

This opened my eyes to:

• E968.5 – Assault by transport vehicle.

• E968.3 – Assault by hot liquid.

• E968.1 – Assault by pushing from a high place. (Questions: How high? How hot? Transporting what?)

While on the subject of injuries in high places, you might consider:

• E840.1 – Accident by powered aircraft at takeoff or landing.

Again, ICD-10 will be more comprehensive.

Looking at injury from burning water skis, we find:

• V91.07 – Burn due to water-skis on fire.

Within which are:

• V91.07XA ... initial encounter.

• V91.07XD ... subsequent encounter.

• V91.07XS ... sequela.

This is not all! V91.07 has many other subcategories:

• V91.0 – Burn due to watercraft on fire.

• V91.01 – Burn due to passenger ship on fire.

• V91.02 – Burn due to fishing boat on fire.

• V91.05 – Burn due to canoe or kayak on fire.

But wait! There is also V91.1 – Crushed between watercraft and other watercraft or other object due to collision. Within which are:

• V91.10 – Crushed between merchant ship and other watercraft or other object due to collision.

• V91.12 – Crushed between fishing boat and other watercraft or other object due to collision.

• V91.15 – Crushed between canoe or kayak and other watercraft or other object due to collision.

Each of these of course includes subcodes for: initial encounter, subsequent encounter, and sequela. (Conversion hysteria caused by paranoid fear of rampaging kayaks?)

The practical advantages to learning all this extend beyond the office. Suppose you’re fishing in a rowboat on a lazy Sunday afternoon when a kayaker waving a flaming blowtorch careens toward you full tilt and you leap overboard. When the Coast Guard pulls you out, you can shout, "V91.05! V91.15!"

In our next installment, we will take up other subsets of external causes of morbidity, including:

• W20 – struck by thrown, projected, or falling object such as:

• W20.0 – Falling object in cave (initial encounter, subsequent encounter, sequela).

• W20.1 – Struck by object due to collapse of building (ditto).

• W28 – Contact with powered lawn mower.

• W60 – Contact with nonvenomous plant thorns and spines and sharp leaves.

Master these. Future columns will cover injuries caused by forces of nature, injuries caused by supernatural means (such as witchcraft, exorcism), assassination (first episode, second episode, sequela), and acute psychosis caused by marauding ICD-10 consultants.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

As the date for implementing ICD-10 gets closer, consulting firms send daily offers to help us adapt to the new diagnostic regime. As a service to the profession, Under My Skin will provide periodic updates to save you consulting fees.

In an earlier column, you learned about new codes like injury from burning water skis. We also covered codes for envenomation by Gila monsters, both unintentional and intentional. You should know that these are already available under ICD-9. No need to wait till next year to use them!

ICD-9-CM E905.0: Venomous snakes and lizards causing poisoning and toxic reactions. These include the following: cobra, copperhead snake, coral snake, fer-de-lance snake, Gila monster, krait, mamba, viper, and several others. Do NOT use this code for bites by nonvenomous snakes and lizards. (That may come back to bite you ... Sorry!)

Anyone who can define a fer-de-lance or a krait is gets extra credit (but no extra payment). If you can either identify a mamba, or dance it, good for you!

ICD-10 naturally amplifies this inadequate taxonomy:

• T63.111 – Toxic effect of venom of Gila monster, accidental (unintentional)

• T63.112 – Toxic effect of venom of Gila monster, intentional (self-harm)

• T63.113 – Toxic effect of venom of Gila monster, assault

• T63.114 – Toxic effect of venom of Gila monster, undetermined

Questions: For the new "assault" code, was the Gila monster the assailant or was its owner? Does "undetermined" mean you don’t really know how you got bitten (come on, was that really an accident – weren’t you petting the Gila kind of roughly?) or that you didn’t determine whether it actually was a Gila monster (because it ran away so fast that that it could have been a marmoset).

There are other ICD-9 codes you can already use (right now!) I recently got a 6-page EMR from a referring clinic (you get those, don’t you?) listing one of the patient’s 14 diagnoses as E968.2: Assault by striking by blunt or thrown object.

This opened my eyes to:

• E968.5 – Assault by transport vehicle.

• E968.3 – Assault by hot liquid.

• E968.1 – Assault by pushing from a high place. (Questions: How high? How hot? Transporting what?)

While on the subject of injuries in high places, you might consider:

• E840.1 – Accident by powered aircraft at takeoff or landing.

Again, ICD-10 will be more comprehensive.

Looking at injury from burning water skis, we find:

• V91.07 – Burn due to water-skis on fire.

Within which are:

• V91.07XA ... initial encounter.

• V91.07XD ... subsequent encounter.

• V91.07XS ... sequela.

This is not all! V91.07 has many other subcategories:

• V91.0 – Burn due to watercraft on fire.

• V91.01 – Burn due to passenger ship on fire.

• V91.02 – Burn due to fishing boat on fire.

• V91.05 – Burn due to canoe or kayak on fire.

But wait! There is also V91.1 – Crushed between watercraft and other watercraft or other object due to collision. Within which are:

• V91.10 – Crushed between merchant ship and other watercraft or other object due to collision.

• V91.12 – Crushed between fishing boat and other watercraft or other object due to collision.

• V91.15 – Crushed between canoe or kayak and other watercraft or other object due to collision.

Each of these of course includes subcodes for: initial encounter, subsequent encounter, and sequela. (Conversion hysteria caused by paranoid fear of rampaging kayaks?)

The practical advantages to learning all this extend beyond the office. Suppose you’re fishing in a rowboat on a lazy Sunday afternoon when a kayaker waving a flaming blowtorch careens toward you full tilt and you leap overboard. When the Coast Guard pulls you out, you can shout, "V91.05! V91.15!"

In our next installment, we will take up other subsets of external causes of morbidity, including:

• W20 – struck by thrown, projected, or falling object such as:

• W20.0 – Falling object in cave (initial encounter, subsequent encounter, sequela).

• W20.1 – Struck by object due to collapse of building (ditto).

• W28 – Contact with powered lawn mower.

• W60 – Contact with nonvenomous plant thorns and spines and sharp leaves.

Master these. Future columns will cover injuries caused by forces of nature, injuries caused by supernatural means (such as witchcraft, exorcism), assassination (first episode, second episode, sequela), and acute psychosis caused by marauding ICD-10 consultants.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

As the date for implementing ICD-10 gets closer, consulting firms send daily offers to help us adapt to the new diagnostic regime. As a service to the profession, Under My Skin will provide periodic updates to save you consulting fees.

In an earlier column, you learned about new codes like injury from burning water skis. We also covered codes for envenomation by Gila monsters, both unintentional and intentional. You should know that these are already available under ICD-9. No need to wait till next year to use them!

ICD-9-CM E905.0: Venomous snakes and lizards causing poisoning and toxic reactions. These include the following: cobra, copperhead snake, coral snake, fer-de-lance snake, Gila monster, krait, mamba, viper, and several others. Do NOT use this code for bites by nonvenomous snakes and lizards. (That may come back to bite you ... Sorry!)

Anyone who can define a fer-de-lance or a krait is gets extra credit (but no extra payment). If you can either identify a mamba, or dance it, good for you!

ICD-10 naturally amplifies this inadequate taxonomy:

• T63.111 – Toxic effect of venom of Gila monster, accidental (unintentional)

• T63.112 – Toxic effect of venom of Gila monster, intentional (self-harm)

• T63.113 – Toxic effect of venom of Gila monster, assault

• T63.114 – Toxic effect of venom of Gila monster, undetermined

Questions: For the new "assault" code, was the Gila monster the assailant or was its owner? Does "undetermined" mean you don’t really know how you got bitten (come on, was that really an accident – weren’t you petting the Gila kind of roughly?) or that you didn’t determine whether it actually was a Gila monster (because it ran away so fast that that it could have been a marmoset).

There are other ICD-9 codes you can already use (right now!) I recently got a 6-page EMR from a referring clinic (you get those, don’t you?) listing one of the patient’s 14 diagnoses as E968.2: Assault by striking by blunt or thrown object.

This opened my eyes to:

• E968.5 – Assault by transport vehicle.

• E968.3 – Assault by hot liquid.

• E968.1 – Assault by pushing from a high place. (Questions: How high? How hot? Transporting what?)

While on the subject of injuries in high places, you might consider:

• E840.1 – Accident by powered aircraft at takeoff or landing.

Again, ICD-10 will be more comprehensive.

Looking at injury from burning water skis, we find:

• V91.07 – Burn due to water-skis on fire.

Within which are:

• V91.07XA ... initial encounter.

• V91.07XD ... subsequent encounter.

• V91.07XS ... sequela.

This is not all! V91.07 has many other subcategories:

• V91.0 – Burn due to watercraft on fire.

• V91.01 – Burn due to passenger ship on fire.

• V91.02 – Burn due to fishing boat on fire.

• V91.05 – Burn due to canoe or kayak on fire.

But wait! There is also V91.1 – Crushed between watercraft and other watercraft or other object due to collision. Within which are:

• V91.10 – Crushed between merchant ship and other watercraft or other object due to collision.

• V91.12 – Crushed between fishing boat and other watercraft or other object due to collision.

• V91.15 – Crushed between canoe or kayak and other watercraft or other object due to collision.

Each of these of course includes subcodes for: initial encounter, subsequent encounter, and sequela. (Conversion hysteria caused by paranoid fear of rampaging kayaks?)

The practical advantages to learning all this extend beyond the office. Suppose you’re fishing in a rowboat on a lazy Sunday afternoon when a kayaker waving a flaming blowtorch careens toward you full tilt and you leap overboard. When the Coast Guard pulls you out, you can shout, "V91.05! V91.15!"

In our next installment, we will take up other subsets of external causes of morbidity, including:

• W20 – struck by thrown, projected, or falling object such as:

• W20.0 – Falling object in cave (initial encounter, subsequent encounter, sequela).

• W20.1 – Struck by object due to collapse of building (ditto).

• W28 – Contact with powered lawn mower.

• W60 – Contact with nonvenomous plant thorns and spines and sharp leaves.

Master these. Future columns will cover injuries caused by forces of nature, injuries caused by supernatural means (such as witchcraft, exorcism), assassination (first episode, second episode, sequela), and acute psychosis caused by marauding ICD-10 consultants.

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002.

Medical Education Library

A supplement to Skin & Allergy News. This supplement was sponsored by Medicis, a division of Valeant Pharmaceuticals.

• Herpes Simplex Virus-1: Prevalence and Diagnosis
• HSL Treatment
• XERESE^® (acyclovir and hydrocortisone) Cream 5%/1%
• Summary and Conclusions
• INDICATION
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Joseph Fowler, MD
University of Louisville
Louisville, Kentucky

Dr. Fowler reported that he is a member of the speakers’ bureau for Valeant Pharmaceuticals and received compensation from Valeant for his assistance in developing the content of this article.

LINKS: Click Here for PDF.

Copyright © by Frontline Medical Communications Inc.

Medical Education Library

A supplement to Skin & Allergy News. This supplement was sponsored by Medicis, a division of Valeant Pharmaceuticals.

• Herpes Simplex Virus-1: Prevalence and Diagnosis
• HSL Treatment
• XERESE^® (acyclovir and hydrocortisone) Cream 5%/1%
• Summary and Conclusions
• INDICATION
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Joseph Fowler, MD
University of Louisville
Louisville, Kentucky

Dr. Fowler reported that he is a member of the speakers’ bureau for Valeant Pharmaceuticals and received compensation from Valeant for his assistance in developing the content of this article.

LINKS: Click Here for PDF.

Copyright © by Frontline Medical Communications Inc.

Medical Education Library

A supplement to Skin & Allergy News. This supplement was sponsored by Medicis, a division of Valeant Pharmaceuticals.

• Herpes Simplex Virus-1: Prevalence and Diagnosis
• HSL Treatment
• XERESE^® (acyclovir and hydrocortisone) Cream 5%/1%
• Summary and Conclusions
• INDICATION
• IMPORTANT SAFETY INFORMATION

Faculty/Faculty Disclosure

Joseph Fowler, MD
University of Louisville
Louisville, Kentucky

Dr. Fowler reported that he is a member of the speakers’ bureau for Valeant Pharmaceuticals and received compensation from Valeant for his assistance in developing the content of this article.

LINKS: Click Here for PDF.

Copyright © by Frontline Medical Communications Inc.

Pressure ulcers have been the focus of an increasing amount of attention over the past few years, appearing everyplace from the local evening news to the government’s list of potentially preventable conditions, where they can carry a pretty steep financial penalty. When I was in residency, for some reason, they just did not seem to be such a common or important issue ... or perhaps we just didn’t pay them their due respect.

These days, they command the attention of legislators, hospital administrators, and physicians alike, not just the attention of nurses and patients, as in days past. Not long ago, the July 2, 2013, issue of Annals of Internal Medicine devoted a significant portion of an issue to the topic of pressure ulcers.

While I already knew pressure ulcers are a significant cause of morbidity, and, infrequently, mortality, I was shocked to learn the extent of this condition – an estimated 1.3 to 3 million adults in this country are affected – and that the cost to treat a pressure ulcer ranges between $37,800 and $70,000 – yes, each! The yearly cost to the U.S. health care system may be as high as $11 billion! That’s a figure I would expect to see with diabetes complications or advanced heart disease.

The article, titled "Pressure Ulcer Treatment Strategies: A Systematic Comparative Effectiveness Review," summarized evidence comparing the efficacy and safety of various treatment strategies for adults with pressure ulcers. Researchers found that using air-fluidized beds, protein supplementation, electrical stimulation, and radiant heat dressings had moderate-strength evidence for healing (Ann. Intern. Med. 2013 July 2;159:39-50).

Pressure ulcer treatment and prevention are too frequently passed on to nursing staff, probably in part because physicians are busy addressing the primary cause for admission and in part because, quite frankly, the nursing staff treat the ulcers on a day-to-day basis and are more likely to have received an in-service educational session about various treatments, not to mention they are often more up-to-date on the latest formulary alternatives for treating various stages of skin breakdown.

But hospitalists should also have some skin in the game, pardon my pun.

There are simple things we can do to help the surveillance for decubitus ulcers, such as having patients turn on their sides when we listen to their lungs, instead if asking them to sit up in bed or listening anteriorly. That way we can take a quick glance at their bottoms when we auscultate their lungs. We can also reposition some patients ourselves when we see them lying in an awkward position. Asking them or their family members to take part in frequent repositioning is yet another simple task. 

With the profound impact pressure ulcers can have on quality of care, risk of complications, medical costs, and even length of stay, hospitalists are in a unique position to positively influence the rate of pressure ulcer formation by having a heightened sense of awareness of our individual patient’s risk and how we can best play a major role in preventing preventable skin breakdown.

 Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

Pressure ulcers have been the focus of an increasing amount of attention over the past few years, appearing everyplace from the local evening news to the government’s list of potentially preventable conditions, where they can carry a pretty steep financial penalty. When I was in residency, for some reason, they just did not seem to be such a common or important issue ... or perhaps we just didn’t pay them their due respect.

These days, they command the attention of legislators, hospital administrators, and physicians alike, not just the attention of nurses and patients, as in days past. Not long ago, the July 2, 2013, issue of Annals of Internal Medicine devoted a significant portion of an issue to the topic of pressure ulcers.

While I already knew pressure ulcers are a significant cause of morbidity, and, infrequently, mortality, I was shocked to learn the extent of this condition – an estimated 1.3 to 3 million adults in this country are affected – and that the cost to treat a pressure ulcer ranges between $37,800 and $70,000 – yes, each! The yearly cost to the U.S. health care system may be as high as $11 billion! That’s a figure I would expect to see with diabetes complications or advanced heart disease.

The article, titled "Pressure Ulcer Treatment Strategies: A Systematic Comparative Effectiveness Review," summarized evidence comparing the efficacy and safety of various treatment strategies for adults with pressure ulcers. Researchers found that using air-fluidized beds, protein supplementation, electrical stimulation, and radiant heat dressings had moderate-strength evidence for healing (Ann. Intern. Med. 2013 July 2;159:39-50).

Pressure ulcer treatment and prevention are too frequently passed on to nursing staff, probably in part because physicians are busy addressing the primary cause for admission and in part because, quite frankly, the nursing staff treat the ulcers on a day-to-day basis and are more likely to have received an in-service educational session about various treatments, not to mention they are often more up-to-date on the latest formulary alternatives for treating various stages of skin breakdown.

But hospitalists should also have some skin in the game, pardon my pun.

There are simple things we can do to help the surveillance for decubitus ulcers, such as having patients turn on their sides when we listen to their lungs, instead if asking them to sit up in bed or listening anteriorly. That way we can take a quick glance at their bottoms when we auscultate their lungs. We can also reposition some patients ourselves when we see them lying in an awkward position. Asking them or their family members to take part in frequent repositioning is yet another simple task. 

With the profound impact pressure ulcers can have on quality of care, risk of complications, medical costs, and even length of stay, hospitalists are in a unique position to positively influence the rate of pressure ulcer formation by having a heightened sense of awareness of our individual patient’s risk and how we can best play a major role in preventing preventable skin breakdown.

 Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

Pressure ulcers have been the focus of an increasing amount of attention over the past few years, appearing everyplace from the local evening news to the government’s list of potentially preventable conditions, where they can carry a pretty steep financial penalty. When I was in residency, for some reason, they just did not seem to be such a common or important issue ... or perhaps we just didn’t pay them their due respect.

These days, they command the attention of legislators, hospital administrators, and physicians alike, not just the attention of nurses and patients, as in days past. Not long ago, the July 2, 2013, issue of Annals of Internal Medicine devoted a significant portion of an issue to the topic of pressure ulcers.

While I already knew pressure ulcers are a significant cause of morbidity, and, infrequently, mortality, I was shocked to learn the extent of this condition – an estimated 1.3 to 3 million adults in this country are affected – and that the cost to treat a pressure ulcer ranges between $37,800 and $70,000 – yes, each! The yearly cost to the U.S. health care system may be as high as $11 billion! That’s a figure I would expect to see with diabetes complications or advanced heart disease.

The article, titled "Pressure Ulcer Treatment Strategies: A Systematic Comparative Effectiveness Review," summarized evidence comparing the efficacy and safety of various treatment strategies for adults with pressure ulcers. Researchers found that using air-fluidized beds, protein supplementation, electrical stimulation, and radiant heat dressings had moderate-strength evidence for healing (Ann. Intern. Med. 2013 July 2;159:39-50).

Pressure ulcer treatment and prevention are too frequently passed on to nursing staff, probably in part because physicians are busy addressing the primary cause for admission and in part because, quite frankly, the nursing staff treat the ulcers on a day-to-day basis and are more likely to have received an in-service educational session about various treatments, not to mention they are often more up-to-date on the latest formulary alternatives for treating various stages of skin breakdown.

But hospitalists should also have some skin in the game, pardon my pun.

There are simple things we can do to help the surveillance for decubitus ulcers, such as having patients turn on their sides when we listen to their lungs, instead if asking them to sit up in bed or listening anteriorly. That way we can take a quick glance at their bottoms when we auscultate their lungs. We can also reposition some patients ourselves when we see them lying in an awkward position. Asking them or their family members to take part in frequent repositioning is yet another simple task. 

With the profound impact pressure ulcers can have on quality of care, risk of complications, medical costs, and even length of stay, hospitalists are in a unique position to positively influence the rate of pressure ulcer formation by having a heightened sense of awareness of our individual patient’s risk and how we can best play a major role in preventing preventable skin breakdown.

 Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ATLANTA – Younger adults with one to three brain metastases survive longer when they are treated with stereotactic radiosurgery alone rather than whole-brain radiation therapy or a combination of both modalities, researchers reported at the annual meeting of the American Society for Radiation Oncology.

Among patients aged 35-50 years, stereotactic radiosurgery (SRS) alone was associated with hazard ratios (HR) for death ranging from 0.46 to 0.64, compared with an age-matched cohort treated with a combination of SRS and whole-brain radiation therapy (WBRT), based on a meta-analysis of data on 389 individual patients in three randomized clinical trials.

For local control, however, the data show a benefit for combined SRS and WBRT. For control of distant brain metastases, the data indicate a benefit for the combined therapies, but only among patients aged 55 years and older, reported Dr. Arjun Sahgal, associate professor of radiation oncology at the University of Toronto.

Courtesy ASTRO

"Our overall survival results favoring radiosurgery alone in younger patients may be explained by the lack of benefit of whole-brain radiation with respect to distant brain control in this cohort, while still exposing them to the harms of whole-brain radiation with respect to memory function and quality of life," he said.

Dr. Sahgal and his colleagues had previously published an aggregate meta-analysis showing that WBRT and SRS improved distant and local brain control but without overall survival benefit compared with SRS alone.

The current study looked at the raw, individual patient data from the three randomized controlled trials included in the original aggregate analysis. The trials included a 2006 study of 132 patients with an endpoint of brain tumor recurrence, a 2009 trial looking at the effect of SRS/WBRT on neurocognitive function in 58 patients, and a 2011 study examining the effect of adjuvant SRS on World Health Organization performance status scores.

The overall median time to local failure in the trials was 6.6 months for SRS alone, compared with 7.7 months for SRS/WBRT. Time to distant failure was also shorter with SRS alone, at a median of 4.7 vs. 7.7 months, respectively. Median time to death, however, was longer with SRS, at 10 vs. 8.2 months.

In a multivariate model for overall survival, the HR was 0.46 for patients at age 35 years, 0.52 at age 40, 0.58 at age 45, and 0.64 at age 50; all hazard ratios had significant confidence intervals. For patients aged 55 years and older, however, the HR for overall survival was not significant.

Patients with only one metastasis had a significantly lower risk of dying, compared with those who had two or three metastases (HR, 0.72).

The risk of local failure was significantly greater with SRS alone for patients aged 45-70.

The risk of new distant metastases was significant with SRS alone for patients aged 55 years and older, and was significantly lower for patients with one metastasis (HR, 0.63) vs. two or more metastases.

Salvage therapy was performed in 28% of patients who underwent SRS alone and 12% of those who received the combined therapies. Distant brain failures occurred in 54% of those in the SRS alone group, compared with 34% of those in the SRS/WBRT group.

Patients who underwent salvage therapy had significantly greater survival rates than those who did not, and this effect did not vary significantly by age, Dr. Sahgal reported.

The authors did not report specific funding sources. Dr. Sahgal reported having no relevant financial disclosures.

ORLANDO – Canadian teenagers with bipolar disorder who reported having headaches also had more severe disease symptoms than did those who did not have headaches, according to an unpublished study.

"We echo previous calls for screening and identification of impairing headaches, such as migraines, among people with mood disorders for two reasons," Dr. Benjamin I. Goldstein, the study’s senior author, said in an interview.

"First, presence of impairing headaches may represent a subtype of bipolar disorder with unique course, characteristics, and perhaps treatment. Second, underrecognition and undertreatment of impairing headaches is well documented among adults with bipolar disorder, and our findings suggest the potential importance of treating these headaches among youth with bipolar disorder as well," said Dr. Goldstein, of Sunnybrook Health Sciences Centre, Toronto, whose poster was presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

© Monkey Business Images Ltd./Thinkstockphotos.com

Most of the studies so far have been done on adults, and not much is known about this possible association among teens, noted Dr. Goldstein and his coinvestigators.

They studied 55 outpatients aged between 13 and 19 years, with bipolar disorder I, II, or not otherwise specified (NOS). Roughly 60% of the patients were female.

Thirty-three of the teens, or 60%, reported headaches, and these individuals had significantly higher rates of intake depressions score, intake mania score, and global functioning score, the researchers found.

Also, these teens had significantly greater identity confusion, anger/depression, and disinhibition/persistence.

Meanwhile, nearly half of patients with BP-II reported headaches, compared with 18% of the patients with BP-I, and 36% of those with BP-NOS.

But psychiatric hospitalizations and psychosis rates showed an opposite trend. Teens without headaches had a significantly higher rate in both categories, compared with those who had headaches.

"This was a somewhat counterintuitive finding, given the other findings of increased illness severity among youth with headaches," Dr. Goldstein wrote. "Bipolar disorder shares numerous features with psychotic disorders as well as affective disorders, such as unipolar depression and anxiety. We could speculate that whatever causal factors are implicated in headaches among youth with bipolar disorder may be more closely linked with the depression and anxiety than they are with psychosis, which is a frequent precipitant of hospitalization."

The researchers wrote that there’s a need for longitudinal studies to identify specific BP symptoms most associated with headaches, in addition to identifying biomarkers that might help with understanding the pathophysiology. There’s also a need to "identify the possible need of specific treatments for youth with BP [who] suffer from comorbid headaches."

One of the study’s limitations was its cross-sectional design and lack of a comparison group, according to the authors.

Dr. Goldstein is a consultant for Bristol-Myers Squibb and has received honoraria from Purdue Pharma.

[email protected]

On Twitter @NaseemSMiller

ORLANDO – Canadian teenagers with bipolar disorder who reported having headaches also had more severe disease symptoms than did those who did not have headaches, according to an unpublished study.

"We echo previous calls for screening and identification of impairing headaches, such as migraines, among people with mood disorders for two reasons," Dr. Benjamin I. Goldstein, the study’s senior author, said in an interview.

"First, presence of impairing headaches may represent a subtype of bipolar disorder with unique course, characteristics, and perhaps treatment. Second, underrecognition and undertreatment of impairing headaches is well documented among adults with bipolar disorder, and our findings suggest the potential importance of treating these headaches among youth with bipolar disorder as well," said Dr. Goldstein, of Sunnybrook Health Sciences Centre, Toronto, whose poster was presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

© Monkey Business Images Ltd./Thinkstockphotos.com

Most of the studies so far have been done on adults, and not much is known about this possible association among teens, noted Dr. Goldstein and his coinvestigators.

They studied 55 outpatients aged between 13 and 19 years, with bipolar disorder I, II, or not otherwise specified (NOS). Roughly 60% of the patients were female.

Thirty-three of the teens, or 60%, reported headaches, and these individuals had significantly higher rates of intake depressions score, intake mania score, and global functioning score, the researchers found.

Also, these teens had significantly greater identity confusion, anger/depression, and disinhibition/persistence.

Meanwhile, nearly half of patients with BP-II reported headaches, compared with 18% of the patients with BP-I, and 36% of those with BP-NOS.

But psychiatric hospitalizations and psychosis rates showed an opposite trend. Teens without headaches had a significantly higher rate in both categories, compared with those who had headaches.

"This was a somewhat counterintuitive finding, given the other findings of increased illness severity among youth with headaches," Dr. Goldstein wrote. "Bipolar disorder shares numerous features with psychotic disorders as well as affective disorders, such as unipolar depression and anxiety. We could speculate that whatever causal factors are implicated in headaches among youth with bipolar disorder may be more closely linked with the depression and anxiety than they are with psychosis, which is a frequent precipitant of hospitalization."

The researchers wrote that there’s a need for longitudinal studies to identify specific BP symptoms most associated with headaches, in addition to identifying biomarkers that might help with understanding the pathophysiology. There’s also a need to "identify the possible need of specific treatments for youth with BP [who] suffer from comorbid headaches."

One of the study’s limitations was its cross-sectional design and lack of a comparison group, according to the authors.

Dr. Goldstein is a consultant for Bristol-Myers Squibb and has received honoraria from Purdue Pharma.

[email protected]

On Twitter @NaseemSMiller

ORLANDO – Canadian teenagers with bipolar disorder who reported having headaches also had more severe disease symptoms than did those who did not have headaches, according to an unpublished study.

"We echo previous calls for screening and identification of impairing headaches, such as migraines, among people with mood disorders for two reasons," Dr. Benjamin I. Goldstein, the study’s senior author, said in an interview.

"First, presence of impairing headaches may represent a subtype of bipolar disorder with unique course, characteristics, and perhaps treatment. Second, underrecognition and undertreatment of impairing headaches is well documented among adults with bipolar disorder, and our findings suggest the potential importance of treating these headaches among youth with bipolar disorder as well," said Dr. Goldstein, of Sunnybrook Health Sciences Centre, Toronto, whose poster was presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

© Monkey Business Images Ltd./Thinkstockphotos.com

Most of the studies so far have been done on adults, and not much is known about this possible association among teens, noted Dr. Goldstein and his coinvestigators.

They studied 55 outpatients aged between 13 and 19 years, with bipolar disorder I, II, or not otherwise specified (NOS). Roughly 60% of the patients were female.

Thirty-three of the teens, or 60%, reported headaches, and these individuals had significantly higher rates of intake depressions score, intake mania score, and global functioning score, the researchers found.

Also, these teens had significantly greater identity confusion, anger/depression, and disinhibition/persistence.

Meanwhile, nearly half of patients with BP-II reported headaches, compared with 18% of the patients with BP-I, and 36% of those with BP-NOS.

But psychiatric hospitalizations and psychosis rates showed an opposite trend. Teens without headaches had a significantly higher rate in both categories, compared with those who had headaches.

"This was a somewhat counterintuitive finding, given the other findings of increased illness severity among youth with headaches," Dr. Goldstein wrote. "Bipolar disorder shares numerous features with psychotic disorders as well as affective disorders, such as unipolar depression and anxiety. We could speculate that whatever causal factors are implicated in headaches among youth with bipolar disorder may be more closely linked with the depression and anxiety than they are with psychosis, which is a frequent precipitant of hospitalization."

The researchers wrote that there’s a need for longitudinal studies to identify specific BP symptoms most associated with headaches, in addition to identifying biomarkers that might help with understanding the pathophysiology. There’s also a need to "identify the possible need of specific treatments for youth with BP [who] suffer from comorbid headaches."

One of the study’s limitations was its cross-sectional design and lack of a comparison group, according to the authors.

Dr. Goldstein is a consultant for Bristol-Myers Squibb and has received honoraria from Purdue Pharma.

[email protected]

On Twitter @NaseemSMiller

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Strange creatures

Ms. L, age 78, is admitted to the inpatient unit for treatment of psychosis and behavioral changes. In the months before this admission, she had visited the emergency room several times for recurrent falls. CT scans of the head show no acute changes; brain and spinal MRI reveal evidence of chronic white matter disease and degenerative changes of the spine. Medical workup is unremarkable and includes evaluation for syncope and ambulation impairments related to degenerative disease of the hip joints.

Ms. L and her family are instructed to follow-up with her primary care physician and a neurologist for neuromuscular workup.

She next presents to her primary care physician, describing hallucinations of strangers walking around her house. Over a few weeks, hallucinations expand to include a fixed hallucination of creatures that she describes as having qualities of insects and plants, “piling up” around her. She describes tactile hallucinations of these creatures crawling on her skin, and she tracks their movements around her. She complains of vivid visual hallucinations of these creatures spinning webs across the room and she says she keeps the lights on at night. Ms. L becomes anxious and depressed, and her insomnia becomes worse.

She is referred for outpatient psychiatric evaluation and treatment.

Ms. L’s family notes lapses of short-term memory, disorganization, and difficulty with tasks such as cooking because she has trouble following steps. These deficits come and go, with periods when she is functional and others during which she experiences considerable confusion. The family is uncertain when these signs and symptoms first appeared, but are clear that these deficits are having an impact on her day-to-day life. She can conduct activities of daily living, but with increasing difficulty—and only with help from her husband for tasks that require complex order and movement.

Over several months, Ms. L’s gait stability decreases and she begins to rely on a walker to keep from falling. On the Montreal Cognitive Assessment screening for cognitive dysfunction, she scores 19 out of 30 (normal range >25). This suggests cognitive impairment greater than expected for her age, compared with normal controls, and, when coupled with her functional impairment, raises the possibility of a diagnosis of dementia with Lewy bodies (DLB).

The authors’ observations

Limited literature exists of placebo-controlled, large-scale studies on DLB treatment. Cholinesterase inhibitors have shown some symptomatic benefit, including for hallucinations.^1-3 Memantine, an N-methyl-d-aspartate receptor blocker, shows mixed results.⁴ Many studies explore the use of neuroleptics for treating hallucinations in psychosis in Parkinson’s disease and Parkinson’s disease dementia (PDD) but, in DLB, the literature primarily consists of case reports.² Much of DLB treatment is inferred and intermixed with studies on PDD.^5,6 

Low-dose clozapine has become a standard treatment for psychosis in Parkinson’s disease based on the findings of several trials.⁶ Despite its side-effect profile, clozapine has been shown to ameliorate hallucinations in PDD without exacerbating parkinsonian symptoms,^7,8 and is the only medication with proven efficacy in PDD.² The French Clozapine Parkinson Study Group demonstrated relief of psychotic symptoms of Parkinson’s disease with clozapine, 6.25 mg/d.⁹ The Clozapine Study Group found complete resolution of hallucinations in some patients within 1 day of initiating clozapine. Among patients in this study who did not see immediate benefit, most showed significant improvement of psychotic symptoms in 1 or 2 weeks.¹⁰

TREATMENT Few options

Ms. L’s psychiatrist and primary care physician start her on a series of medications. Donepezil is initiated for suspected dementia. We begin a trial of quetiapine to address the hallucinations, but the drug makes her movement symptoms worse. Risperidone also is tried but, again, the drugs make movement symptoms, particularly gait instability, tremor, and rigidity worse without alleviating the hallucinations. Neuroleptics seem to exacerbate confusion. Because of worsening depressive symptoms and our concern over possible pseudodementia, we try several selective serotonin reuptake inhibitors (SSRIs) and mirtazapine. Antidepressants have little effect on her depressive symptoms and do not improve hallucinations or insomnia.

Ms. L’s signs and symptoms become worse over the next few months, with more severe hallucinations, agitation, insomnia, and gait instability. Her agitation over the hallucinations increases and she begins pouring bleach around herself in bed and spraying her house with toxic bug spray. Ms. L’s family brings her to the hospital after they observe her scratching the hallucinatory creatures off of her skin with a razor blade and trying to pry them out of her mouth with a piece of metal.

In the hospital, medical and neurologic workups rule out organic causes for her symptoms and signs. MRI is consistent with imaging from 6 months earlier. Focal neurologic signs are absent. Blood work is within normal limits, failing to reveal any pathology that would suggest a cause for her symptoms and signs, such as syphilis, vitamin deficiency, and Lyme disease.

Ms. L’s symptoms were consistent with consensus guideline criteria for a clinical diagnosis of DLB (Table 1).^11-18

She is started on low-dose quetiapine, which she tolerates poorly with worsening confusion, rigidity, tremor, and gait instability. Because other agents failed, Ms. L’s providers and family decide on a trial of clozapine.

Within 24 hours after the first dose of clozapine, 25 mg, sleep improves, the tactile component of hallucinations diminish, and she begins to spend increasing periods of time “observing the creatures” rather than fighting with them.

Over the next few days, Ms. L’s attitude towards the creatures changes. Now, as she sits observing them intently, the hallucinations evolve: rather than tormenting her and causing distress, the plant-creatures burst apart and a miniature knight on horseback charges out. The rest of the creatures then gather into a rank and file and the knight leads them to the nearest exit.

Clozapine is titrated to 50 mg/d, which she tolerates well without exacerbation of cognitive symptoms or movement disorder. The only notable adverse effect at the time of her discharge is sialorrhea.

The authors’ observations

Ideally, in psychosis, antipsychotics eliminate positive symptoms such as hallucinations and delusions. In DLB, the aim is to alleviate the agitation and suffering brought on by the psychotic symptoms without exacerbating other motor and cognitive symptoms. The hallucinations are obstinate, and it is a well-known quality of this disorder that patients are exceptionally susceptible to a range of antipsychotic side effects including cognitive impairment, fatigue, neuroleptic malignant syndrome, and parkinsonism.¹⁹

Treatment in DLB requires trial and error, and medications with fewer associated risks should be administered first. Patients with DLB treated with neuroleptics have an increased risk of death compared with those who are not treated.¹⁹ Moreover, prescribing information for clozapine includes a black-box warning that the drug:

• is not approved for dementia-related psychosis and
• is associated with an increased risk of death in elderly patients with these conditions, similar to what is seen with other neuroleptics.²⁰

Despite these well-known concerns, it remains difficult for clinicians not to try to treat the distress caused by these symptoms.

We chose clozapine for Ms. L because:

• other neuroleptics failed
• acetylcholinesterase inhibitors did not alleviate Ms. L’s psychosis and associated behavioral disturbance
• there is substantial evidence that the drug can be effective in Parkinson’s disease with psychosis.

There is controversy regarding use of clozapine in DLB. In one case series, clozapine trigger extreme neuroleptic reactions in some patients, similar to what occurs with other second-generation antipsychotics.²¹ Another case series provides examples of the drug’s efficacy in treating hallucinations and delusions with minimal adverse effects.²²

It is important to emphasize that Ms. L’s hallucinations did not go away; rather, they changed to a more benign presentation that she could manage and, occasionally, found pleasant. Ultimately, her agitation—the primary target of treatment—improved markedly with the arrival of the knight in shining armor.

Treatment recommendations

If neuropsychiatric symptoms in DLB are the primary concern of the patient and family, we recommend the following:

• Begin treatment with a cholinesterase inhibitor. The best evidence exists for rivastigmine and donepezil. These drugs have a low risk of side effects, which are primarily gastrointestinal effects with some reports of worsening extrapyramidal symptoms.^23-25
• If the patient obtains minimal benefit or develops a significant adverse effect from cholinesterase inhibitors, consider memantine. Its efficacy is under examination and results are mixed; it can be used in combination with cholinesterase inhibitors.^26-28
• If psychotic symptoms are upsetting and refractory to other therapies, consider antipsychotics. Avoid first-generation antipsychotics. The American Psychiatric Association recommends aripiprazole or quetiapine initially, although there is little evidence comparing neuroleptics in DLB.²⁹ Because of its risks, reserve clozapine for refractory cases. An exception might be made for patients sensitive to extrapyramidal effects, in whom clozapine could be considered earlier.

There are no formal neuroleptic dosing guidelines beyond a general urging towards minimalism. Mosimann and McKeith³⁰ recommend clozapine, 12.5 mg/d; olanzapine, 2.5 mg/d; risperidone, 0.25 mg/d; or quetiapine, 12.5 mg/d. Such dosages might be effective while producing only minimal side effects.^9,31

SSRIs and other antidepressants have not been shown to improve neuropsychiatric symptoms, and often are poorly tolerated.³²

One study found efficacy with electroconvulsive therapy and transcranial magnetic stimulation in treatment-resistant patients.³³

In addition to these treatments, nonpharmaceutical interventions should be employed from the earliest stages of diagnosis and treatment (Table 2). See the Figure for an algorithm for treating DLB. These include educational and behavioral interventions, social support, psychological interventions, and environmental therapies and modifications.

OUTCOME New friends

The creatures return from time to time, Ms. L reports, but are no longer upsetting because the white knight (a sort of mental deus ex machina) leads the once-terrifying things away. She describes the hallucination as a kind of zoological observation, refers to the creatures that once horrified her as “her friends,” and chuckles as she observes their natural history. This new, far more benign hallucination becomes a mainstay of her symptoms, and she is discharged to the care of her husband and family.

Soon after her discharge, her hallucinations resolved completely, but returned briefly when Ms. L resumed smoking cigarettes because smoking is known to lower clozapine serum levels.³⁴ 

Bottom Line

Consider a low dosage of a neuroleptic when a patient suffers significant distress and behavioral disturbance related to psychotic symptoms in dementia with Lewy bodies and those problems are not relieved by other agents. Low-dose clozapine is an option for refractory psychotic symptoms or in patients with severe extrapyramidal sensitivity. Start low, and go slow.

Related Resources

• Bishnoi RJ, Grossberg GT, Manepalli J. Differentiating Alzheimer’s disease from dementia with Lewy bodies. Current Psychiatry. 2012;11(11):22-27.
• McKeith I, Emre M. Management of Parkinson’s disease dementia and dementia with Lewy bodies. In: Emre M, ed. Cognitive impairment and dementia in Parkinson’s disease. Oxford, United Kingdom: Oxford University Press; 2010:245-256.

Drug Brand Names

Aripiprazole • Abilify              Mirtazapine • Remeron

Clozapine • Clozaril                Olanzapine • Zyprexa

Donepezil • Aricept                Quetiapine • Seroquel

Haloperidol • Haldol               Risperidone • Risperdal

Memantine • Namenda           Rivastigmine • Exelon

Disclosures

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

CASE Strange creatures

Ms. L, age 78, is admitted to the inpatient unit for treatment of psychosis and behavioral changes. In the months before this admission, she had visited the emergency room several times for recurrent falls. CT scans of the head show no acute changes; brain and spinal MRI reveal evidence of chronic white matter disease and degenerative changes of the spine. Medical workup is unremarkable and includes evaluation for syncope and ambulation impairments related to degenerative disease of the hip joints.

Ms. L and her family are instructed to follow-up with her primary care physician and a neurologist for neuromuscular workup.

She next presents to her primary care physician, describing hallucinations of strangers walking around her house. Over a few weeks, hallucinations expand to include a fixed hallucination of creatures that she describes as having qualities of insects and plants, “piling up” around her. She describes tactile hallucinations of these creatures crawling on her skin, and she tracks their movements around her. She complains of vivid visual hallucinations of these creatures spinning webs across the room and she says she keeps the lights on at night. Ms. L becomes anxious and depressed, and her insomnia becomes worse.

She is referred for outpatient psychiatric evaluation and treatment.

Ms. L’s family notes lapses of short-term memory, disorganization, and difficulty with tasks such as cooking because she has trouble following steps. These deficits come and go, with periods when she is functional and others during which she experiences considerable confusion. The family is uncertain when these signs and symptoms first appeared, but are clear that these deficits are having an impact on her day-to-day life. She can conduct activities of daily living, but with increasing difficulty—and only with help from her husband for tasks that require complex order and movement.

Over several months, Ms. L’s gait stability decreases and she begins to rely on a walker to keep from falling. On the Montreal Cognitive Assessment screening for cognitive dysfunction, she scores 19 out of 30 (normal range >25). This suggests cognitive impairment greater than expected for her age, compared with normal controls, and, when coupled with her functional impairment, raises the possibility of a diagnosis of dementia with Lewy bodies (DLB).

The authors’ observations

Limited literature exists of placebo-controlled, large-scale studies on DLB treatment. Cholinesterase inhibitors have shown some symptomatic benefit, including for hallucinations.^1-3 Memantine, an N-methyl-d-aspartate receptor blocker, shows mixed results.⁴ Many studies explore the use of neuroleptics for treating hallucinations in psychosis in Parkinson’s disease and Parkinson’s disease dementia (PDD) but, in DLB, the literature primarily consists of case reports.² Much of DLB treatment is inferred and intermixed with studies on PDD.^5,6 

Low-dose clozapine has become a standard treatment for psychosis in Parkinson’s disease based on the findings of several trials.⁶ Despite its side-effect profile, clozapine has been shown to ameliorate hallucinations in PDD without exacerbating parkinsonian symptoms,^7,8 and is the only medication with proven efficacy in PDD.² The French Clozapine Parkinson Study Group demonstrated relief of psychotic symptoms of Parkinson’s disease with clozapine, 6.25 mg/d.⁹ The Clozapine Study Group found complete resolution of hallucinations in some patients within 1 day of initiating clozapine. Among patients in this study who did not see immediate benefit, most showed significant improvement of psychotic symptoms in 1 or 2 weeks.¹⁰

TREATMENT Few options

Ms. L’s psychiatrist and primary care physician start her on a series of medications. Donepezil is initiated for suspected dementia. We begin a trial of quetiapine to address the hallucinations, but the drug makes her movement symptoms worse. Risperidone also is tried but, again, the drugs make movement symptoms, particularly gait instability, tremor, and rigidity worse without alleviating the hallucinations. Neuroleptics seem to exacerbate confusion. Because of worsening depressive symptoms and our concern over possible pseudodementia, we try several selective serotonin reuptake inhibitors (SSRIs) and mirtazapine. Antidepressants have little effect on her depressive symptoms and do not improve hallucinations or insomnia.

Ms. L’s signs and symptoms become worse over the next few months, with more severe hallucinations, agitation, insomnia, and gait instability. Her agitation over the hallucinations increases and she begins pouring bleach around herself in bed and spraying her house with toxic bug spray. Ms. L’s family brings her to the hospital after they observe her scratching the hallucinatory creatures off of her skin with a razor blade and trying to pry them out of her mouth with a piece of metal.

In the hospital, medical and neurologic workups rule out organic causes for her symptoms and signs. MRI is consistent with imaging from 6 months earlier. Focal neurologic signs are absent. Blood work is within normal limits, failing to reveal any pathology that would suggest a cause for her symptoms and signs, such as syphilis, vitamin deficiency, and Lyme disease.

Ms. L’s symptoms were consistent with consensus guideline criteria for a clinical diagnosis of DLB (Table 1).^11-18

She is started on low-dose quetiapine, which she tolerates poorly with worsening confusion, rigidity, tremor, and gait instability. Because other agents failed, Ms. L’s providers and family decide on a trial of clozapine.

Within 24 hours after the first dose of clozapine, 25 mg, sleep improves, the tactile component of hallucinations diminish, and she begins to spend increasing periods of time “observing the creatures” rather than fighting with them.

Over the next few days, Ms. L’s attitude towards the creatures changes. Now, as she sits observing them intently, the hallucinations evolve: rather than tormenting her and causing distress, the plant-creatures burst apart and a miniature knight on horseback charges out. The rest of the creatures then gather into a rank and file and the knight leads them to the nearest exit.

Clozapine is titrated to 50 mg/d, which she tolerates well without exacerbation of cognitive symptoms or movement disorder. The only notable adverse effect at the time of her discharge is sialorrhea.

The authors’ observations

Ideally, in psychosis, antipsychotics eliminate positive symptoms such as hallucinations and delusions. In DLB, the aim is to alleviate the agitation and suffering brought on by the psychotic symptoms without exacerbating other motor and cognitive symptoms. The hallucinations are obstinate, and it is a well-known quality of this disorder that patients are exceptionally susceptible to a range of antipsychotic side effects including cognitive impairment, fatigue, neuroleptic malignant syndrome, and parkinsonism.¹⁹

Treatment in DLB requires trial and error, and medications with fewer associated risks should be administered first. Patients with DLB treated with neuroleptics have an increased risk of death compared with those who are not treated.¹⁹ Moreover, prescribing information for clozapine includes a black-box warning that the drug:

• is not approved for dementia-related psychosis and
• is associated with an increased risk of death in elderly patients with these conditions, similar to what is seen with other neuroleptics.²⁰

Despite these well-known concerns, it remains difficult for clinicians not to try to treat the distress caused by these symptoms.

We chose clozapine for Ms. L because:

• other neuroleptics failed
• acetylcholinesterase inhibitors did not alleviate Ms. L’s psychosis and associated behavioral disturbance
• there is substantial evidence that the drug can be effective in Parkinson’s disease with psychosis.

There is controversy regarding use of clozapine in DLB. In one case series, clozapine trigger extreme neuroleptic reactions in some patients, similar to what occurs with other second-generation antipsychotics.²¹ Another case series provides examples of the drug’s efficacy in treating hallucinations and delusions with minimal adverse effects.²²

It is important to emphasize that Ms. L’s hallucinations did not go away; rather, they changed to a more benign presentation that she could manage and, occasionally, found pleasant. Ultimately, her agitation—the primary target of treatment—improved markedly with the arrival of the knight in shining armor.

Treatment recommendations

If neuropsychiatric symptoms in DLB are the primary concern of the patient and family, we recommend the following:

• Begin treatment with a cholinesterase inhibitor. The best evidence exists for rivastigmine and donepezil. These drugs have a low risk of side effects, which are primarily gastrointestinal effects with some reports of worsening extrapyramidal symptoms.^23-25
• If the patient obtains minimal benefit or develops a significant adverse effect from cholinesterase inhibitors, consider memantine. Its efficacy is under examination and results are mixed; it can be used in combination with cholinesterase inhibitors.^26-28
• If psychotic symptoms are upsetting and refractory to other therapies, consider antipsychotics. Avoid first-generation antipsychotics. The American Psychiatric Association recommends aripiprazole or quetiapine initially, although there is little evidence comparing neuroleptics in DLB.²⁹ Because of its risks, reserve clozapine for refractory cases. An exception might be made for patients sensitive to extrapyramidal effects, in whom clozapine could be considered earlier.

There are no formal neuroleptic dosing guidelines beyond a general urging towards minimalism. Mosimann and McKeith³⁰ recommend clozapine, 12.5 mg/d; olanzapine, 2.5 mg/d; risperidone, 0.25 mg/d; or quetiapine, 12.5 mg/d. Such dosages might be effective while producing only minimal side effects.^9,31

SSRIs and other antidepressants have not been shown to improve neuropsychiatric symptoms, and often are poorly tolerated.³²

One study found efficacy with electroconvulsive therapy and transcranial magnetic stimulation in treatment-resistant patients.³³

In addition to these treatments, nonpharmaceutical interventions should be employed from the earliest stages of diagnosis and treatment (Table 2). See the Figure for an algorithm for treating DLB. These include educational and behavioral interventions, social support, psychological interventions, and environmental therapies and modifications.

OUTCOME New friends

The creatures return from time to time, Ms. L reports, but are no longer upsetting because the white knight (a sort of mental deus ex machina) leads the once-terrifying things away. She describes the hallucination as a kind of zoological observation, refers to the creatures that once horrified her as “her friends,” and chuckles as she observes their natural history. This new, far more benign hallucination becomes a mainstay of her symptoms, and she is discharged to the care of her husband and family.

Soon after her discharge, her hallucinations resolved completely, but returned briefly when Ms. L resumed smoking cigarettes because smoking is known to lower clozapine serum levels.³⁴ 

Bottom Line

Consider a low dosage of a neuroleptic when a patient suffers significant distress and behavioral disturbance related to psychotic symptoms in dementia with Lewy bodies and those problems are not relieved by other agents. Low-dose clozapine is an option for refractory psychotic symptoms or in patients with severe extrapyramidal sensitivity. Start low, and go slow.

Related Resources

• Bishnoi RJ, Grossberg GT, Manepalli J. Differentiating Alzheimer’s disease from dementia with Lewy bodies. Current Psychiatry. 2012;11(11):22-27.
• McKeith I, Emre M. Management of Parkinson’s disease dementia and dementia with Lewy bodies. In: Emre M, ed. Cognitive impairment and dementia in Parkinson’s disease. Oxford, United Kingdom: Oxford University Press; 2010:245-256.

Drug Brand Names

Aripiprazole • Abilify              Mirtazapine • Remeron

Clozapine • Clozaril                Olanzapine • Zyprexa

Donepezil • Aricept                Quetiapine • Seroquel

Haloperidol • Haldol               Risperidone • Risperdal

Memantine • Namenda           Rivastigmine • Exelon

Disclosures

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

CASE Strange creatures

Ms. L, age 78, is admitted to the inpatient unit for treatment of psychosis and behavioral changes. In the months before this admission, she had visited the emergency room several times for recurrent falls. CT scans of the head show no acute changes; brain and spinal MRI reveal evidence of chronic white matter disease and degenerative changes of the spine. Medical workup is unremarkable and includes evaluation for syncope and ambulation impairments related to degenerative disease of the hip joints.

Ms. L and her family are instructed to follow-up with her primary care physician and a neurologist for neuromuscular workup.

She next presents to her primary care physician, describing hallucinations of strangers walking around her house. Over a few weeks, hallucinations expand to include a fixed hallucination of creatures that she describes as having qualities of insects and plants, “piling up” around her. She describes tactile hallucinations of these creatures crawling on her skin, and she tracks their movements around her. She complains of vivid visual hallucinations of these creatures spinning webs across the room and she says she keeps the lights on at night. Ms. L becomes anxious and depressed, and her insomnia becomes worse.

She is referred for outpatient psychiatric evaluation and treatment.

Ms. L’s family notes lapses of short-term memory, disorganization, and difficulty with tasks such as cooking because she has trouble following steps. These deficits come and go, with periods when she is functional and others during which she experiences considerable confusion. The family is uncertain when these signs and symptoms first appeared, but are clear that these deficits are having an impact on her day-to-day life. She can conduct activities of daily living, but with increasing difficulty—and only with help from her husband for tasks that require complex order and movement.

Over several months, Ms. L’s gait stability decreases and she begins to rely on a walker to keep from falling. On the Montreal Cognitive Assessment screening for cognitive dysfunction, she scores 19 out of 30 (normal range >25). This suggests cognitive impairment greater than expected for her age, compared with normal controls, and, when coupled with her functional impairment, raises the possibility of a diagnosis of dementia with Lewy bodies (DLB).

The authors’ observations

Limited literature exists of placebo-controlled, large-scale studies on DLB treatment. Cholinesterase inhibitors have shown some symptomatic benefit, including for hallucinations.^1-3 Memantine, an N-methyl-d-aspartate receptor blocker, shows mixed results.⁴ Many studies explore the use of neuroleptics for treating hallucinations in psychosis in Parkinson’s disease and Parkinson’s disease dementia (PDD) but, in DLB, the literature primarily consists of case reports.² Much of DLB treatment is inferred and intermixed with studies on PDD.^5,6 

Low-dose clozapine has become a standard treatment for psychosis in Parkinson’s disease based on the findings of several trials.⁶ Despite its side-effect profile, clozapine has been shown to ameliorate hallucinations in PDD without exacerbating parkinsonian symptoms,^7,8 and is the only medication with proven efficacy in PDD.² The French Clozapine Parkinson Study Group demonstrated relief of psychotic symptoms of Parkinson’s disease with clozapine, 6.25 mg/d.⁹ The Clozapine Study Group found complete resolution of hallucinations in some patients within 1 day of initiating clozapine. Among patients in this study who did not see immediate benefit, most showed significant improvement of psychotic symptoms in 1 or 2 weeks.¹⁰

TREATMENT Few options

Ms. L’s psychiatrist and primary care physician start her on a series of medications. Donepezil is initiated for suspected dementia. We begin a trial of quetiapine to address the hallucinations, but the drug makes her movement symptoms worse. Risperidone also is tried but, again, the drugs make movement symptoms, particularly gait instability, tremor, and rigidity worse without alleviating the hallucinations. Neuroleptics seem to exacerbate confusion. Because of worsening depressive symptoms and our concern over possible pseudodementia, we try several selective serotonin reuptake inhibitors (SSRIs) and mirtazapine. Antidepressants have little effect on her depressive symptoms and do not improve hallucinations or insomnia.

Ms. L’s signs and symptoms become worse over the next few months, with more severe hallucinations, agitation, insomnia, and gait instability. Her agitation over the hallucinations increases and she begins pouring bleach around herself in bed and spraying her house with toxic bug spray. Ms. L’s family brings her to the hospital after they observe her scratching the hallucinatory creatures off of her skin with a razor blade and trying to pry them out of her mouth with a piece of metal.

In the hospital, medical and neurologic workups rule out organic causes for her symptoms and signs. MRI is consistent with imaging from 6 months earlier. Focal neurologic signs are absent. Blood work is within normal limits, failing to reveal any pathology that would suggest a cause for her symptoms and signs, such as syphilis, vitamin deficiency, and Lyme disease.

Ms. L’s symptoms were consistent with consensus guideline criteria for a clinical diagnosis of DLB (Table 1).^11-18

She is started on low-dose quetiapine, which she tolerates poorly with worsening confusion, rigidity, tremor, and gait instability. Because other agents failed, Ms. L’s providers and family decide on a trial of clozapine.

Within 24 hours after the first dose of clozapine, 25 mg, sleep improves, the tactile component of hallucinations diminish, and she begins to spend increasing periods of time “observing the creatures” rather than fighting with them.

Over the next few days, Ms. L’s attitude towards the creatures changes. Now, as she sits observing them intently, the hallucinations evolve: rather than tormenting her and causing distress, the plant-creatures burst apart and a miniature knight on horseback charges out. The rest of the creatures then gather into a rank and file and the knight leads them to the nearest exit.

Clozapine is titrated to 50 mg/d, which she tolerates well without exacerbation of cognitive symptoms or movement disorder. The only notable adverse effect at the time of her discharge is sialorrhea.

The authors’ observations

Ideally, in psychosis, antipsychotics eliminate positive symptoms such as hallucinations and delusions. In DLB, the aim is to alleviate the agitation and suffering brought on by the psychotic symptoms without exacerbating other motor and cognitive symptoms. The hallucinations are obstinate, and it is a well-known quality of this disorder that patients are exceptionally susceptible to a range of antipsychotic side effects including cognitive impairment, fatigue, neuroleptic malignant syndrome, and parkinsonism.¹⁹

Treatment in DLB requires trial and error, and medications with fewer associated risks should be administered first. Patients with DLB treated with neuroleptics have an increased risk of death compared with those who are not treated.¹⁹ Moreover, prescribing information for clozapine includes a black-box warning that the drug:

• is not approved for dementia-related psychosis and
• is associated with an increased risk of death in elderly patients with these conditions, similar to what is seen with other neuroleptics.²⁰

Despite these well-known concerns, it remains difficult for clinicians not to try to treat the distress caused by these symptoms.

We chose clozapine for Ms. L because:

• other neuroleptics failed
• acetylcholinesterase inhibitors did not alleviate Ms. L’s psychosis and associated behavioral disturbance
• there is substantial evidence that the drug can be effective in Parkinson’s disease with psychosis.

There is controversy regarding use of clozapine in DLB. In one case series, clozapine trigger extreme neuroleptic reactions in some patients, similar to what occurs with other second-generation antipsychotics.²¹ Another case series provides examples of the drug’s efficacy in treating hallucinations and delusions with minimal adverse effects.²²

It is important to emphasize that Ms. L’s hallucinations did not go away; rather, they changed to a more benign presentation that she could manage and, occasionally, found pleasant. Ultimately, her agitation—the primary target of treatment—improved markedly with the arrival of the knight in shining armor.

Treatment recommendations

If neuropsychiatric symptoms in DLB are the primary concern of the patient and family, we recommend the following:

• Begin treatment with a cholinesterase inhibitor. The best evidence exists for rivastigmine and donepezil. These drugs have a low risk of side effects, which are primarily gastrointestinal effects with some reports of worsening extrapyramidal symptoms.^23-25
• If the patient obtains minimal benefit or develops a significant adverse effect from cholinesterase inhibitors, consider memantine. Its efficacy is under examination and results are mixed; it can be used in combination with cholinesterase inhibitors.^26-28
• If psychotic symptoms are upsetting and refractory to other therapies, consider antipsychotics. Avoid first-generation antipsychotics. The American Psychiatric Association recommends aripiprazole or quetiapine initially, although there is little evidence comparing neuroleptics in DLB.²⁹ Because of its risks, reserve clozapine for refractory cases. An exception might be made for patients sensitive to extrapyramidal effects, in whom clozapine could be considered earlier.

There are no formal neuroleptic dosing guidelines beyond a general urging towards minimalism. Mosimann and McKeith³⁰ recommend clozapine, 12.5 mg/d; olanzapine, 2.5 mg/d; risperidone, 0.25 mg/d; or quetiapine, 12.5 mg/d. Such dosages might be effective while producing only minimal side effects.^9,31

SSRIs and other antidepressants have not been shown to improve neuropsychiatric symptoms, and often are poorly tolerated.³²

One study found efficacy with electroconvulsive therapy and transcranial magnetic stimulation in treatment-resistant patients.³³

In addition to these treatments, nonpharmaceutical interventions should be employed from the earliest stages of diagnosis and treatment (Table 2). See the Figure for an algorithm for treating DLB. These include educational and behavioral interventions, social support, psychological interventions, and environmental therapies and modifications.

OUTCOME New friends

The creatures return from time to time, Ms. L reports, but are no longer upsetting because the white knight (a sort of mental deus ex machina) leads the once-terrifying things away. She describes the hallucination as a kind of zoological observation, refers to the creatures that once horrified her as “her friends,” and chuckles as she observes their natural history. This new, far more benign hallucination becomes a mainstay of her symptoms, and she is discharged to the care of her husband and family.

Soon after her discharge, her hallucinations resolved completely, but returned briefly when Ms. L resumed smoking cigarettes because smoking is known to lower clozapine serum levels.³⁴ 

Bottom Line

Consider a low dosage of a neuroleptic when a patient suffers significant distress and behavioral disturbance related to psychotic symptoms in dementia with Lewy bodies and those problems are not relieved by other agents. Low-dose clozapine is an option for refractory psychotic symptoms or in patients with severe extrapyramidal sensitivity. Start low, and go slow.

Related Resources

• Bishnoi RJ, Grossberg GT, Manepalli J. Differentiating Alzheimer’s disease from dementia with Lewy bodies. Current Psychiatry. 2012;11(11):22-27.
• McKeith I, Emre M. Management of Parkinson’s disease dementia and dementia with Lewy bodies. In: Emre M, ed. Cognitive impairment and dementia in Parkinson’s disease. Oxford, United Kingdom: Oxford University Press; 2010:245-256.

Drug Brand Names

Aripiprazole • Abilify              Mirtazapine • Remeron

Clozapine • Clozaril                Olanzapine • Zyprexa

Donepezil • Aricept                Quetiapine • Seroquel

Haloperidol • Haldol               Risperidone • Risperdal

Memantine • Namenda           Rivastigmine • Exelon

Disclosures

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