FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.

Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).

Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.

The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.

The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.

Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.

Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).

Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.

The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.

The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.

Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – Exercise training boosts the longevity of patients with heart failure.

Although results from several prior randomized, controlled trials had already shown a mortality benefit from exercise training for heart failure patients, these findings have now been confirmed by a meta-analysis that used the original, individual patient raw data collected in 20 separate randomized, controlled trials that together involved more than 4,000 patients. The results showed that an exercise-training intervention run for at least 3 weeks produced a statistically significant, relative reduction in all-cause mortality of 18%, compared with similar patients who had been randomized to usual care without an exercise program, Oriana Ciani, Ph.D., reported at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Mitchel L. Zoler/Frontline Medical News

The individual patient data meta-analysis using results from randomized, controlled trials also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization in heart failure patients during at least 6 months’ follow-up of exercise programs that lasted for at least 3 weeks, said Dr. Ciani, a health technology researcher at the University of Exeter (England).

Her analysis also showed no suggestion of heterogeneity for each of these two beneficial effects from exercise programs, regardless of patients’ age, sex, or baseline levels of left ventricular ejection fraction, heart failure etiology, functional status, or exercise capacity. “No evidence was found to support a differential treatment effect from exercise-based intervention across patient subgroups,” she said.

The Exercise Training for Chronic Heart Failure (ExTraMATCH II) meta-analysis used data collected in randomized trials published through 2014 that involved at least 50 patients, used an exercise intervention for at least 3 weeks, and had follow-up for at least 6 months. Dr. Ciani and her associates identified 20 studies that included a total of 4,043 heart failure patients who fulfilled these criteria and for whom the researchers from the studies were willing to share individual patient data.

The analysis also showed a median time to all-cause mortality of 605 days among patients who received exercise training and 615 days in the controls, and a median time to first all-cause hospitalization of 229 days with exercise training and 241 days in the controls. The percentage of patients who were hospitalized during follow-up was reduced by an absolute 3.8% for those in the exercise group, compared with the controls.

Although the type of exercise intervention used varied among the 20 studies, most involved aerobic training, and some also used resistance training, Dr. Ciani said. She said she plans additional analyses of the data she has collected to examine the impact of exercise in heart failure patients on cardiovascular mortality, heart failure hospitalization, and a combined endpoint of all-cause death and all-cause hospitalization.

[email protected]

On Twitter @mitchelzoler

Developing your practice policies and sharing them with your patients is essential to building long-term, trusting relationships. Having a clear starting point helps avert disagreement down the road and allows patients to feel comfortable knowing what they are getting in to, which will provide a foundation on which you and the patient can focus on clinical matters.

What’s in a policy?
Policies should cover administrative aspects of care, such as mandated disclosures; relevant Health Insurance Portability and Accountability Act and Health Information Technology for Economic and Clinical Health Act information; hospital privilege status; and fees and payment policies. Your policies also will touch on areas where business overlaps with patient care, such as confidentiality and its limits, communication methods outside of session, and the risks and benefits of treatment (Table).
 

Address communication and billing policies for complex scenarios. Although these scenarios might not come up often, if you wait until you are confronted with the situation, the patient might (rightly) feel that she (he) wasn’t properly informed before giving consent. For example:

• For college students. Do you try to build college students’ autonomy by sending them all billing statements directly? If not, how will you handle the diagnosis code that appears on the statement, which their parents could see? What if the student doesn’t act on the statements—will you start mailing them to the parents? Should you mandate that you be able to talk with their parents?
• For adolescents. Consider whether you will allow them to communicate with you directly. Will they be able to e-mail you? How will you communicate with her (his) parents if your relationship is primarily with the teenager? How will you handle medication changes when the teenager prefers you keep everything private, but the parents have the right to informed consent?
• Will you charge for the time it takes you to talk with other providers (CPT 90887); review reports (CPT 90885); for e-mails or phone calls that are only a minute, or 10 minutes (e-mail, CPT 99444; brief phone calls, CPT 99441); or out-of-session refills? What if an insurance company does, or doesn’t, cover these codes? Is it different for patients you see occasionally for medication checks and for those whom you see weekly for therapy?

Psychodynamics of policies
Nowhere does being both a business and a service intersect more than when discussing how much you charge, and for what services. Patients may have little understanding of all the time you spend on their care, and why you choose to bill or not to bill for certain services. They could naturally develop transference reactions based on your policies, or might not even read them and just sign off, which also can give you useful clinical data.

Patients should review and accept your policies before the first appointment is booked. However, it is still meaningful to extend the opportunity to discuss them with a patient at the first session—but if they do not want to ask questions or discuss administrative matters, then follow their lead. By at least offering, this conveys to the patient that you wish to develop a trusting relationship, and that you are open to addressing conflicts or confusion at the beginning.

A valuable investment in time
Spending a bit of time now to create or review your current policies will save a lot of time—and perhaps money or legal action—later. If you can’t think of every scenario or issue today, don’t fret. Your experience in practice will inevitably lead you to recalibrate and update your policies. What’s most important is that your patients know where you stand and that they can trust you over the long-term.

Developing your practice policies and sharing them with your patients is essential to building long-term, trusting relationships. Having a clear starting point helps avert disagreement down the road and allows patients to feel comfortable knowing what they are getting in to, which will provide a foundation on which you and the patient can focus on clinical matters.

What’s in a policy?
Policies should cover administrative aspects of care, such as mandated disclosures; relevant Health Insurance Portability and Accountability Act and Health Information Technology for Economic and Clinical Health Act information; hospital privilege status; and fees and payment policies. Your policies also will touch on areas where business overlaps with patient care, such as confidentiality and its limits, communication methods outside of session, and the risks and benefits of treatment (Table).
 

Address communication and billing policies for complex scenarios. Although these scenarios might not come up often, if you wait until you are confronted with the situation, the patient might (rightly) feel that she (he) wasn’t properly informed before giving consent. For example:

• For college students. Do you try to build college students’ autonomy by sending them all billing statements directly? If not, how will you handle the diagnosis code that appears on the statement, which their parents could see? What if the student doesn’t act on the statements—will you start mailing them to the parents? Should you mandate that you be able to talk with their parents?
• For adolescents. Consider whether you will allow them to communicate with you directly. Will they be able to e-mail you? How will you communicate with her (his) parents if your relationship is primarily with the teenager? How will you handle medication changes when the teenager prefers you keep everything private, but the parents have the right to informed consent?
• Will you charge for the time it takes you to talk with other providers (CPT 90887); review reports (CPT 90885); for e-mails or phone calls that are only a minute, or 10 minutes (e-mail, CPT 99444; brief phone calls, CPT 99441); or out-of-session refills? What if an insurance company does, or doesn’t, cover these codes? Is it different for patients you see occasionally for medication checks and for those whom you see weekly for therapy?

Psychodynamics of policies
Nowhere does being both a business and a service intersect more than when discussing how much you charge, and for what services. Patients may have little understanding of all the time you spend on their care, and why you choose to bill or not to bill for certain services. They could naturally develop transference reactions based on your policies, or might not even read them and just sign off, which also can give you useful clinical data.

Patients should review and accept your policies before the first appointment is booked. However, it is still meaningful to extend the opportunity to discuss them with a patient at the first session—but if they do not want to ask questions or discuss administrative matters, then follow their lead. By at least offering, this conveys to the patient that you wish to develop a trusting relationship, and that you are open to addressing conflicts or confusion at the beginning.

A valuable investment in time
Spending a bit of time now to create or review your current policies will save a lot of time—and perhaps money or legal action—later. If you can’t think of every scenario or issue today, don’t fret. Your experience in practice will inevitably lead you to recalibrate and update your policies. What’s most important is that your patients know where you stand and that they can trust you over the long-term.

Developing your practice policies and sharing them with your patients is essential to building long-term, trusting relationships. Having a clear starting point helps avert disagreement down the road and allows patients to feel comfortable knowing what they are getting in to, which will provide a foundation on which you and the patient can focus on clinical matters.

What’s in a policy?
Policies should cover administrative aspects of care, such as mandated disclosures; relevant Health Insurance Portability and Accountability Act and Health Information Technology for Economic and Clinical Health Act information; hospital privilege status; and fees and payment policies. Your policies also will touch on areas where business overlaps with patient care, such as confidentiality and its limits, communication methods outside of session, and the risks and benefits of treatment (Table).
 

Address communication and billing policies for complex scenarios. Although these scenarios might not come up often, if you wait until you are confronted with the situation, the patient might (rightly) feel that she (he) wasn’t properly informed before giving consent. For example:

• For college students. Do you try to build college students’ autonomy by sending them all billing statements directly? If not, how will you handle the diagnosis code that appears on the statement, which their parents could see? What if the student doesn’t act on the statements—will you start mailing them to the parents? Should you mandate that you be able to talk with their parents?
• For adolescents. Consider whether you will allow them to communicate with you directly. Will they be able to e-mail you? How will you communicate with her (his) parents if your relationship is primarily with the teenager? How will you handle medication changes when the teenager prefers you keep everything private, but the parents have the right to informed consent?
• Will you charge for the time it takes you to talk with other providers (CPT 90887); review reports (CPT 90885); for e-mails or phone calls that are only a minute, or 10 minutes (e-mail, CPT 99444; brief phone calls, CPT 99441); or out-of-session refills? What if an insurance company does, or doesn’t, cover these codes? Is it different for patients you see occasionally for medication checks and for those whom you see weekly for therapy?

Psychodynamics of policies
Nowhere does being both a business and a service intersect more than when discussing how much you charge, and for what services. Patients may have little understanding of all the time you spend on their care, and why you choose to bill or not to bill for certain services. They could naturally develop transference reactions based on your policies, or might not even read them and just sign off, which also can give you useful clinical data.

Patients should review and accept your policies before the first appointment is booked. However, it is still meaningful to extend the opportunity to discuss them with a patient at the first session—but if they do not want to ask questions or discuss administrative matters, then follow their lead. By at least offering, this conveys to the patient that you wish to develop a trusting relationship, and that you are open to addressing conflicts or confusion at the beginning.

A valuable investment in time
Spending a bit of time now to create or review your current policies will save a lot of time—and perhaps money or legal action—later. If you can’t think of every scenario or issue today, don’t fret. Your experience in practice will inevitably lead you to recalibrate and update your policies. What’s most important is that your patients know where you stand and that they can trust you over the long-term.

CHICAGO—One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the previous 30 days, Rhea C. Pimentel, MD, said at the 65th Annual Meeting of the American College of Cardiology.

The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) patients with this event died during their stroke hospitalization, compared with six of 83 (7%) patients whose strokes were not temporally related to atrial fibrillation, said Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.

Data from the Framingham Heart Study and other sources suggest that stroke in patients with atrial fibrillation entails about double the mortality rate of strokes in patients without atrial fibrillation. Mortality associated with atrial fibrillation–related stroke in the study was probably much higher because the hospital serves as a comprehensive stroke center and admits patients from across the Midwest, she said.

Dr. Pimentel reported data on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This study is described as the largest patient series ever reported. Patients’ mean age was 73, and 41% were women. The mean CHADS2 score was 3.96 and the mean CHA2DS2-VASc score was 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of atrial fibrillation, and a fifth were on an oral anticoagulant—warfarin, in 70% of cases—at the time of their stroke.

Investigators defined a stroke-related atrial fibrillation episode as a total of at least one hour spent in atrial fibrillation at 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal atrial fibrillation. They typically fulfilled the one-hour atrial fibrillation requirement with multiple short, self-terminated episodes rather than with an hour-long episode.

Being on an oral anticoagulant had no impact on in-hospital mortality rate, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel presented the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be enlightening,” she said.

She and her coinvestigators also plan to subdivide their 30-day study period into five-day segments to learn how soon after an atrial fibrillation episode the strokes occurred. Researchers at Stanford University have reported that the greatest stroke risk in patients with atrial fibrillation occurs during the first five days after an atrial fibrillation episode. Dr. Pimentel’s group would like to confirm that observation.

In addition, because it remains an unresolved question whether any amount of atrial fibrillation is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of six minutes of atrial fibrillation rather than one hour during the 30 days prior to stroke.

—Bruce Jancin

CHICAGO—One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the previous 30 days, Rhea C. Pimentel, MD, said at the 65th Annual Meeting of the American College of Cardiology.

The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) patients with this event died during their stroke hospitalization, compared with six of 83 (7%) patients whose strokes were not temporally related to atrial fibrillation, said Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.

Data from the Framingham Heart Study and other sources suggest that stroke in patients with atrial fibrillation entails about double the mortality rate of strokes in patients without atrial fibrillation. Mortality associated with atrial fibrillation–related stroke in the study was probably much higher because the hospital serves as a comprehensive stroke center and admits patients from across the Midwest, she said.

Dr. Pimentel reported data on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This study is described as the largest patient series ever reported. Patients’ mean age was 73, and 41% were women. The mean CHADS2 score was 3.96 and the mean CHA2DS2-VASc score was 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of atrial fibrillation, and a fifth were on an oral anticoagulant—warfarin, in 70% of cases—at the time of their stroke.

Investigators defined a stroke-related atrial fibrillation episode as a total of at least one hour spent in atrial fibrillation at 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal atrial fibrillation. They typically fulfilled the one-hour atrial fibrillation requirement with multiple short, self-terminated episodes rather than with an hour-long episode.

Being on an oral anticoagulant had no impact on in-hospital mortality rate, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel presented the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be enlightening,” she said.

She and her coinvestigators also plan to subdivide their 30-day study period into five-day segments to learn how soon after an atrial fibrillation episode the strokes occurred. Researchers at Stanford University have reported that the greatest stroke risk in patients with atrial fibrillation occurs during the first five days after an atrial fibrillation episode. Dr. Pimentel’s group would like to confirm that observation.

In addition, because it remains an unresolved question whether any amount of atrial fibrillation is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of six minutes of atrial fibrillation rather than one hour during the 30 days prior to stroke.

—Bruce Jancin

CHICAGO—One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the previous 30 days, Rhea C. Pimentel, MD, said at the 65th Annual Meeting of the American College of Cardiology.

The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) patients with this event died during their stroke hospitalization, compared with six of 83 (7%) patients whose strokes were not temporally related to atrial fibrillation, said Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.

Data from the Framingham Heart Study and other sources suggest that stroke in patients with atrial fibrillation entails about double the mortality rate of strokes in patients without atrial fibrillation. Mortality associated with atrial fibrillation–related stroke in the study was probably much higher because the hospital serves as a comprehensive stroke center and admits patients from across the Midwest, she said.

Dr. Pimentel reported data on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This study is described as the largest patient series ever reported. Patients’ mean age was 73, and 41% were women. The mean CHADS2 score was 3.96 and the mean CHA2DS2-VASc score was 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of atrial fibrillation, and a fifth were on an oral anticoagulant—warfarin, in 70% of cases—at the time of their stroke.

Investigators defined a stroke-related atrial fibrillation episode as a total of at least one hour spent in atrial fibrillation at 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal atrial fibrillation. They typically fulfilled the one-hour atrial fibrillation requirement with multiple short, self-terminated episodes rather than with an hour-long episode.

Being on an oral anticoagulant had no impact on in-hospital mortality rate, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel presented the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be enlightening,” she said.

She and her coinvestigators also plan to subdivide their 30-day study period into five-day segments to learn how soon after an atrial fibrillation episode the strokes occurred. Researchers at Stanford University have reported that the greatest stroke risk in patients with atrial fibrillation occurs during the first five days after an atrial fibrillation episode. Dr. Pimentel’s group would like to confirm that observation.

In addition, because it remains an unresolved question whether any amount of atrial fibrillation is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of six minutes of atrial fibrillation rather than one hour during the 30 days prior to stroke.

—Bruce Jancin

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of:

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention,¹ as it is popularly thought to be.

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they articulate and explain the meaning of the fortune?

Insight. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of:

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention,¹ as it is popularly thought to be.

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they articulate and explain the meaning of the fortune?

Insight. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of:

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention,¹ as it is popularly thought to be.

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they articulate and explain the meaning of the fortune?

Insight. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

A biopsy of the submandibular gland may provide an accurate diagnosis of Parkinson’s disease and dementia with Lewy bodies (DLB), according to a study published March 30 in the Journal of Parkinson’s Disease. If confirmed, the results could improve patient recruitment for clinical trials.

Parkinson’s disease and DLB are widely misdiagnosed. Misdiagnosis may occur in approximately 50% of patients with Parkinson’s disease who are within the first five years of symptom onset, according to the researchers. Between 15% and 25% of neuropathologically defined patients with DLB receive a diagnosis of DLB during life.

“The low diagnostic accuracy, during life, for DLB has made it difficult to conduct effective clinical trials of possibly helpful new drugs,” said Thomas G. Beach, MD, PhD, Head and Senior Scientist at the Civin Laboratory for Neuropathology and Director of the Brain and Body Donation Program at Banner Sun Health Research Institute in Phoenix. “With better diagnostic accuracy, clinical trials would have a higher chance of success and could be done more quickly and at a lesser cost,” Dr. Beach said.

Brain biopsies are highly accurate for detecting Parkinson’s disease and DLB, but they entail a high risk of complications. Previous data suggested a high prevalence of submandibular gland synucleinopathy in patients with Parkinson’s disease. “This new work shows, in autopsies, that the submandibular gland also has the same signature alpha-synuclein pathology in a high proportion of subjects diagnosed during life with DLB,” said Dr. Beach.

Thomas G. Beach, MD, PhD

Dr. Beach and colleagues performed brain necropsies and neuropathologic examinations on elderly subjects with and without CNS Lewy-type pathology who had donated their bodies. The investigators stained submandibular gland sections with an immunohistochemical method to find Lewy-type α-synucleinopathy (LTS). Subjects with Lewy body disorders included 47 with Parkinson’s disease, 28 with DLB, nine with incidental Lewy-body disease, 33 with Alzheimer’s disease with Lewy bodies, and two with progressive supranuclear palsy with Lewy bodies. The 79 control subjects without CNS LTS included 15 with Alzheimer’s disease, 12 with progressive supranuclear palsy, two with corticobasal degeneration, and two with multiple system atrophy.

Submandibular gland LTS was present in 42 of 47 (89%) individuals with Parkinson’s disease, 20 of 28 (71%) people with DLB, four of 33 people with Alzheimer’s disease with Lewy bodies, one of nine people with incidental Lewy-body disease, and none of the 110 controls.

Needle biopsy of the submandibular gland may be useful as diagnostic biomarker or a biomarker of progression in Parkinson’s disease, said the researchers. In addition, the technique may improve diagnostic sensitivity for DLB and be a potential prognostic indicator. “The next step will be to do biopsies of the submandibular gland in living people with DLB to confirm these autopsy results,” Dr. Beach said.

—Erica Robinson

A biopsy of the submandibular gland may provide an accurate diagnosis of Parkinson’s disease and dementia with Lewy bodies (DLB), according to a study published March 30 in the Journal of Parkinson’s Disease. If confirmed, the results could improve patient recruitment for clinical trials.

Parkinson’s disease and DLB are widely misdiagnosed. Misdiagnosis may occur in approximately 50% of patients with Parkinson’s disease who are within the first five years of symptom onset, according to the researchers. Between 15% and 25% of neuropathologically defined patients with DLB receive a diagnosis of DLB during life.

“The low diagnostic accuracy, during life, for DLB has made it difficult to conduct effective clinical trials of possibly helpful new drugs,” said Thomas G. Beach, MD, PhD, Head and Senior Scientist at the Civin Laboratory for Neuropathology and Director of the Brain and Body Donation Program at Banner Sun Health Research Institute in Phoenix. “With better diagnostic accuracy, clinical trials would have a higher chance of success and could be done more quickly and at a lesser cost,” Dr. Beach said.

Brain biopsies are highly accurate for detecting Parkinson’s disease and DLB, but they entail a high risk of complications. Previous data suggested a high prevalence of submandibular gland synucleinopathy in patients with Parkinson’s disease. “This new work shows, in autopsies, that the submandibular gland also has the same signature alpha-synuclein pathology in a high proportion of subjects diagnosed during life with DLB,” said Dr. Beach.

Thomas G. Beach, MD, PhD

Dr. Beach and colleagues performed brain necropsies and neuropathologic examinations on elderly subjects with and without CNS Lewy-type pathology who had donated their bodies. The investigators stained submandibular gland sections with an immunohistochemical method to find Lewy-type α-synucleinopathy (LTS). Subjects with Lewy body disorders included 47 with Parkinson’s disease, 28 with DLB, nine with incidental Lewy-body disease, 33 with Alzheimer’s disease with Lewy bodies, and two with progressive supranuclear palsy with Lewy bodies. The 79 control subjects without CNS LTS included 15 with Alzheimer’s disease, 12 with progressive supranuclear palsy, two with corticobasal degeneration, and two with multiple system atrophy.

Submandibular gland LTS was present in 42 of 47 (89%) individuals with Parkinson’s disease, 20 of 28 (71%) people with DLB, four of 33 people with Alzheimer’s disease with Lewy bodies, one of nine people with incidental Lewy-body disease, and none of the 110 controls.

Needle biopsy of the submandibular gland may be useful as diagnostic biomarker or a biomarker of progression in Parkinson’s disease, said the researchers. In addition, the technique may improve diagnostic sensitivity for DLB and be a potential prognostic indicator. “The next step will be to do biopsies of the submandibular gland in living people with DLB to confirm these autopsy results,” Dr. Beach said.

—Erica Robinson

A biopsy of the submandibular gland may provide an accurate diagnosis of Parkinson’s disease and dementia with Lewy bodies (DLB), according to a study published March 30 in the Journal of Parkinson’s Disease. If confirmed, the results could improve patient recruitment for clinical trials.

Parkinson’s disease and DLB are widely misdiagnosed. Misdiagnosis may occur in approximately 50% of patients with Parkinson’s disease who are within the first five years of symptom onset, according to the researchers. Between 15% and 25% of neuropathologically defined patients with DLB receive a diagnosis of DLB during life.

“The low diagnostic accuracy, during life, for DLB has made it difficult to conduct effective clinical trials of possibly helpful new drugs,” said Thomas G. Beach, MD, PhD, Head and Senior Scientist at the Civin Laboratory for Neuropathology and Director of the Brain and Body Donation Program at Banner Sun Health Research Institute in Phoenix. “With better diagnostic accuracy, clinical trials would have a higher chance of success and could be done more quickly and at a lesser cost,” Dr. Beach said.

Brain biopsies are highly accurate for detecting Parkinson’s disease and DLB, but they entail a high risk of complications. Previous data suggested a high prevalence of submandibular gland synucleinopathy in patients with Parkinson’s disease. “This new work shows, in autopsies, that the submandibular gland also has the same signature alpha-synuclein pathology in a high proportion of subjects diagnosed during life with DLB,” said Dr. Beach.

Thomas G. Beach, MD, PhD

Dr. Beach and colleagues performed brain necropsies and neuropathologic examinations on elderly subjects with and without CNS Lewy-type pathology who had donated their bodies. The investigators stained submandibular gland sections with an immunohistochemical method to find Lewy-type α-synucleinopathy (LTS). Subjects with Lewy body disorders included 47 with Parkinson’s disease, 28 with DLB, nine with incidental Lewy-body disease, 33 with Alzheimer’s disease with Lewy bodies, and two with progressive supranuclear palsy with Lewy bodies. The 79 control subjects without CNS LTS included 15 with Alzheimer’s disease, 12 with progressive supranuclear palsy, two with corticobasal degeneration, and two with multiple system atrophy.

Submandibular gland LTS was present in 42 of 47 (89%) individuals with Parkinson’s disease, 20 of 28 (71%) people with DLB, four of 33 people with Alzheimer’s disease with Lewy bodies, one of nine people with incidental Lewy-body disease, and none of the 110 controls.

Needle biopsy of the submandibular gland may be useful as diagnostic biomarker or a biomarker of progression in Parkinson’s disease, said the researchers. In addition, the technique may improve diagnostic sensitivity for DLB and be a potential prognostic indicator. “The next step will be to do biopsies of the submandibular gland in living people with DLB to confirm these autopsy results,” Dr. Beach said.

—Erica Robinson

PARIS – Patients undergoing complex percutaneous intervention for acute coronary syndrome fared significantly better with prasugrel than clopidogrel as antiplatelet therapy in the large, real-world PROMETHEUS registry, Dr. Jaya Chandrasekhar reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Cumulative 1-year all-cause mortality was 8% with clopidogrel (Plavix), compared with 2% with prasugrel (Effient), for an adjusted 42% relative risk reduction favoring the more potent oral thienopyridine.

Bruce Jancin/Frontline Medical News

Moreover, the 1-year composite MACE (major adverse cardiac events) outcome comprising death, MI, stroke, or unplanned revascularization occurred in 24.3% of the clopidogrel group, compared with 13.3% of the prasugrel group. That translates to an adjusted 22% relative risk reduction, noted Dr. Chandrasekhar of Mount Sinai Medical Center in New York.

Bleeding rates were similar in the prasugrel and clopidogrel groups, she added.

She stressed that these findings must be viewed as hypothesis-generating rather than definitive, since PROMETHEUS was not a randomized clinical trial. Rather, it was a retrospective observational study of 19,914 patients who underwent PCI for ACS at eight major U.S. medical centers, 20% of whom got prasugrel, 80% clopidogrel. Half of the patients had a complex PCI, defined by Dr. Chandrasekhar and coinvestigators as one targeting the left main coronary artery, any bifurcation lesion, any moderate or severely calcified lesion, or an intervention resulting in a total stent length of 30 mm or longer.

The complex PCI patients were significantly older, by just under 2 years. They had higher rates of diabetes, unstable angina, and multivessel disease, and were more likely to receive at least one second-generation drug-eluting stent.

In a multivariate analysis adjusted for these potential confounders as well as race, body mass index, kidney function, hypertension, hemoglobin, previous PCI, and concomitant use of bivalirudin, the benefits of prasugrel over clopidogrel at 1 year remained significant in patients who underwent complex PCI. In contrast, among the 10,179 ACS patients who underwent noncomplex PCI, the trends favoring lower mortality and MACE in the prasugrel group no longer attained statistical significance upon multivariate adjustment, she said.

Discussant Dr. Pascal Meier said that registry data on prasugrel are inevitably biased because physicians don’t give the drug to patients older than 75 or patients who have had a prior stroke, are low weight, or low risk.

“Do you think there’s any way we can adjust for this bias?” asked Dr. Meier of University Hospital, Geneva.

Dr. Chandrasekhar conceded the possibility of unrecognized confounders.

“I think no matter what statistical methods you use, there will be that potential for bias. This is a real-world study. We understand that physicians and operators select their patients very carefully and the healthier ones get prasugrel rather than clopidogrel.”

She reported having no financial conflicts regarding this study. PROMETHEUS was sponsored and funded by Daiichi Sankyo and Eli Lilly.

[email protected]

PARIS – Patients undergoing complex percutaneous intervention for acute coronary syndrome fared significantly better with prasugrel than clopidogrel as antiplatelet therapy in the large, real-world PROMETHEUS registry, Dr. Jaya Chandrasekhar reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Cumulative 1-year all-cause mortality was 8% with clopidogrel (Plavix), compared with 2% with prasugrel (Effient), for an adjusted 42% relative risk reduction favoring the more potent oral thienopyridine.

Bruce Jancin/Frontline Medical News

Moreover, the 1-year composite MACE (major adverse cardiac events) outcome comprising death, MI, stroke, or unplanned revascularization occurred in 24.3% of the clopidogrel group, compared with 13.3% of the prasugrel group. That translates to an adjusted 22% relative risk reduction, noted Dr. Chandrasekhar of Mount Sinai Medical Center in New York.

Bleeding rates were similar in the prasugrel and clopidogrel groups, she added.

She stressed that these findings must be viewed as hypothesis-generating rather than definitive, since PROMETHEUS was not a randomized clinical trial. Rather, it was a retrospective observational study of 19,914 patients who underwent PCI for ACS at eight major U.S. medical centers, 20% of whom got prasugrel, 80% clopidogrel. Half of the patients had a complex PCI, defined by Dr. Chandrasekhar and coinvestigators as one targeting the left main coronary artery, any bifurcation lesion, any moderate or severely calcified lesion, or an intervention resulting in a total stent length of 30 mm or longer.

The complex PCI patients were significantly older, by just under 2 years. They had higher rates of diabetes, unstable angina, and multivessel disease, and were more likely to receive at least one second-generation drug-eluting stent.

In a multivariate analysis adjusted for these potential confounders as well as race, body mass index, kidney function, hypertension, hemoglobin, previous PCI, and concomitant use of bivalirudin, the benefits of prasugrel over clopidogrel at 1 year remained significant in patients who underwent complex PCI. In contrast, among the 10,179 ACS patients who underwent noncomplex PCI, the trends favoring lower mortality and MACE in the prasugrel group no longer attained statistical significance upon multivariate adjustment, she said.

Discussant Dr. Pascal Meier said that registry data on prasugrel are inevitably biased because physicians don’t give the drug to patients older than 75 or patients who have had a prior stroke, are low weight, or low risk.

“Do you think there’s any way we can adjust for this bias?” asked Dr. Meier of University Hospital, Geneva.

Dr. Chandrasekhar conceded the possibility of unrecognized confounders.

“I think no matter what statistical methods you use, there will be that potential for bias. This is a real-world study. We understand that physicians and operators select their patients very carefully and the healthier ones get prasugrel rather than clopidogrel.”

She reported having no financial conflicts regarding this study. PROMETHEUS was sponsored and funded by Daiichi Sankyo and Eli Lilly.

[email protected]

PARIS – Patients undergoing complex percutaneous intervention for acute coronary syndrome fared significantly better with prasugrel than clopidogrel as antiplatelet therapy in the large, real-world PROMETHEUS registry, Dr. Jaya Chandrasekhar reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Cumulative 1-year all-cause mortality was 8% with clopidogrel (Plavix), compared with 2% with prasugrel (Effient), for an adjusted 42% relative risk reduction favoring the more potent oral thienopyridine.

Bruce Jancin/Frontline Medical News

Moreover, the 1-year composite MACE (major adverse cardiac events) outcome comprising death, MI, stroke, or unplanned revascularization occurred in 24.3% of the clopidogrel group, compared with 13.3% of the prasugrel group. That translates to an adjusted 22% relative risk reduction, noted Dr. Chandrasekhar of Mount Sinai Medical Center in New York.

Bleeding rates were similar in the prasugrel and clopidogrel groups, she added.

She stressed that these findings must be viewed as hypothesis-generating rather than definitive, since PROMETHEUS was not a randomized clinical trial. Rather, it was a retrospective observational study of 19,914 patients who underwent PCI for ACS at eight major U.S. medical centers, 20% of whom got prasugrel, 80% clopidogrel. Half of the patients had a complex PCI, defined by Dr. Chandrasekhar and coinvestigators as one targeting the left main coronary artery, any bifurcation lesion, any moderate or severely calcified lesion, or an intervention resulting in a total stent length of 30 mm or longer.

The complex PCI patients were significantly older, by just under 2 years. They had higher rates of diabetes, unstable angina, and multivessel disease, and were more likely to receive at least one second-generation drug-eluting stent.

In a multivariate analysis adjusted for these potential confounders as well as race, body mass index, kidney function, hypertension, hemoglobin, previous PCI, and concomitant use of bivalirudin, the benefits of prasugrel over clopidogrel at 1 year remained significant in patients who underwent complex PCI. In contrast, among the 10,179 ACS patients who underwent noncomplex PCI, the trends favoring lower mortality and MACE in the prasugrel group no longer attained statistical significance upon multivariate adjustment, she said.

Discussant Dr. Pascal Meier said that registry data on prasugrel are inevitably biased because physicians don’t give the drug to patients older than 75 or patients who have had a prior stroke, are low weight, or low risk.

“Do you think there’s any way we can adjust for this bias?” asked Dr. Meier of University Hospital, Geneva.

Dr. Chandrasekhar conceded the possibility of unrecognized confounders.

“I think no matter what statistical methods you use, there will be that potential for bias. This is a real-world study. We understand that physicians and operators select their patients very carefully and the healthier ones get prasugrel rather than clopidogrel.”

She reported having no financial conflicts regarding this study. PROMETHEUS was sponsored and funded by Daiichi Sankyo and Eli Lilly.

[email protected]

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams

Dear Dr. Mossman,

All the psychiatrists at our clinic agree: It is hard to remember when our patients who take an antipsychotic are due for metabolic monitoring, and it’s even harder to get many of them to follow through with timely blood tests. For many, stopping their medication would be a bad idea. If we keep a patient on an antipsychotic and a metabolic problem results, how serious is our malpractice liability risk?

Submitted by “Dr. V”

Antipsychotics, the mainstay of treatment for schizophrenia,¹ put patients at risk of gaining weight and developing metabolic syndrome, including type 2 diabetes mellitus, hypertension, and dyslipidemia.² Second-generation antipsychotics are the biggest offenders, but taking a first-generation antipsychotic also can lead to these adverse effects.³

Most psychiatrists are aware of these risks and prefer that their patients do not experience them. However, many psychiatrists neglect proper monitoring or, like Dr. V, find it hard to ensure it happens and thus worry about clinical deterioration if patients stop taking an antipsychotic.⁴ If you are in the same situation as Dr. V, what medicolegal risks are you facing?

To answer this question, we will:

• review the clinical guidelines and standards for monitoring metabolic effects of antipsychotics
• examine how well (or poorly) physicians adhere to these standards
• discuss what “standard of care” means and how a practice guideline affects the standard effects
• propose how psychiatrists can do better at policing the metabolic effects of antipsychotics.

I’ll be watching you: Following guidelines
Several medical specialty societies have published guidelines for monitoring the metabolic effects of antipsychotics.^5-8 These guidelines instruct physicians to obtain a thorough personal and family history; consider metabolic risks when starting a medication; and monitor weight, waist circumference, blood pressure, glucose, hemoglobin A_1c, and lipids at various intervals. They also advise referral for management of detected metabolic problems.

Although the recommendations seem clear, many physicians don’t follow them. A 2012 meta-analysis of 48 studies, covering >200,000 antipsychotic-treated patients, showed that baseline measurements of cholesterol, glucose, and weight occurred in <50% of cases.⁹ A more recent review found that, among adults with a serious mental illness, the rate of lipid testing varied from 6% to 85% and for glucose monitoring, between 18% and 75%.¹⁰ In the first years after antipsychotic monitoring guidelines were established, they had only a modest impact on practice,^9,11 and some studies showed the guidelines made no difference at all.^12-14

Monitoring compliance varies with the type of insurance coverage patients have but remains suboptimal among the commercially insured,¹¹ Medicaid patients,^14-16 and veterans.^17,18 Studies on antipsychotic treatment in children, adolescents, patients with dementia, and patients with an intellectual disability show insufficient monitoring as well.^{9,14,17,19-21} The reasons for these gaps are manifold, but one commonly cited factor is uncertainty about whether the psychiatrist or primary care physician should handle monitoring.²²

Every claim you stake: The ‘standard of care’
In a medical malpractice case, the party claiming injury must show that the accused physician failed to follow “the generally recognized practices and procedures which would be exercised by ordinary competent practitioners in a defendant doctor’s field of medicine under the same or similar circumstances.”²³ In the studies mentioned above,^9-14 a large fraction of psychiatrists—many of whom, we can presume, are “competent practitioners”—don’t follow the antipsychotic monitoring guidelines in actual practice. Could failing to follow those guidelines still be the basis for a successful lawsuit?

The answer seems to be ‘yes.’ Published legal decisions describe malpractice lawsuits alleging physicians’ failure to follow antipsychotic guidelines,^24,25 and online advertisements show that attorneys believe such cases can generate a payout.^26,27 This may seem odd, given what studies say about psychiatrists’ monitoring practices. But determining the “standard of care” in a malpractice case is not an empirical question; it is a legal matter that is decided based on the testimony of expert witnesses.²⁸ Here, customary practice matters, but it’s not the whole story.

Although the standard of care against which courts measure a physician’s actions “is that of a reasonably prudent practitioner …, The degree of care actually practiced by members of the profession is only some evidence of what is reasonably prudent—it is not dispositive.”²⁹ To support their opinion concerning the standard of care, testifying medical witnesses sometimes use practice guidelines. In this case, an explanation of why a particular guideline was chosen is crucial.³⁰

Using guidelines to establish the standard is controversial. On one hand, using guidelines in malpractice litigation allows for some consistency about expectations of practitioners.^31,32 Although guidelines are not identical to evidenced-based medicine, they generally reflect an evidence-based expert consensus about sound medical practice. If a hospital uses a guideline to train its employees, the guideline provides the courts with clear information on what should have happened.^33,34 Laws in some states allow clinicians to invoke their adherence to a guideline in defense against malpractice claims.³⁵

On the other hand, critics contend that guidelines may not set an accurate standard for the quality of care, nor do they necessarily reflect a proper balance of the conflicting interests of patients and the health care system.³⁶ The American Psychiatric Association states that its practice guidelines “are not intended to serve or be construed as a ‘standard of medical care.’”³⁷

Conformity is not the only measure of prudent practice, and following guidelines does not immunize a clinician from lawsuit if a particular clinical situation demands a different course of action.³² Guidelines can be costly to implement,³⁶ compliance with guidelines generally is low,³⁵ and national guidelines do not necessarily improve the quality of care.³⁸ Last, relying on guidelines to determine the standard of care might stifle innovation or development of alternate approaches by silencing viewpoints.^39,40 Table 1^33-35,39,41 (page 60)summarizes variables that make a guideline more indicative of the standard of care.
 

Every step you take: Better monitoring
Medical professionals often are slow to update their practice to reflect new knowledge about optimal treatment. But practice guidelines influence the court’s views about the standard of care, and Dr. V’s question shows that he and his colleagues agree that metabolic status needs to be better monitored when patients take antipsychotic drugs. The following discussion and Table 2^42-45 offer suggestions for how psychiatrists and their practice settings could better accomplish this.

Electronic health records (EHRs). Monitor­ing health indices often is the largest hurdle that health care professionals face.⁴⁶ However, large health care systems with EHRs are in a good position to develop and implement automated computer routines that track which patients need monitoring and note due dates, abnormal results, and management interventions.⁴² Some studies suggest that monitoring rates in both inpatient⁴⁷ and outpatient⁴⁸ settings improve with built-in EHR reminders. However, if a system uses too many reminders, the resulting “alert fatigue” will limit their value.²² Providing individual feedback about monitoring practices may enhance physicians’ buy-in to reminder systems.⁴⁸
 

Integrated care systems can improve patient outcomes, particularly antipsychotic monitoring. Advantages include shared funding streams, a unified medical record, coordinated scheduling of psychiatric and primary care appointments, and addressing blood-draw refusals.⁴³ More frequent primary care visits make antipsychotic monitoring more likely.¹¹ Ultimately, integrated care could resolve problems related to determining which clinicians are responsible for monitoring and managing adverse metabolic effects.

Third-party payers. Managed care interventions also could improve monitoring rates.⁴⁴ Prior authorization often requires physicians to obtain appropriate lab work. Insurers might contact physicians with educational interventions, including free webinars, provider alerts, and letters about monitoring rates in their region. Some insurers also provide disease management programs for patients and their caregivers.

Individual and small group practices. Psychiatrists who practice outside a large health care system might designate 2 months each year as “physical health months.” In the “Let’s Get Physical” program,⁴⁵ physicians were given longer appointment times during these months to address metabolic monitoring, provide education about managing side effects of medication, and encourage better diets and exercise.

Overall, the best techniques might be those implicit to good doctoring: clear and open communication with patients, effective patient education, respect of informed consent, and thorough follow-up.⁴⁹

Dear Dr. Mossman,

All the psychiatrists at our clinic agree: It is hard to remember when our patients who take an antipsychotic are due for metabolic monitoring, and it’s even harder to get many of them to follow through with timely blood tests. For many, stopping their medication would be a bad idea. If we keep a patient on an antipsychotic and a metabolic problem results, how serious is our malpractice liability risk?

Submitted by “Dr. V”

Antipsychotics, the mainstay of treatment for schizophrenia,¹ put patients at risk of gaining weight and developing metabolic syndrome, including type 2 diabetes mellitus, hypertension, and dyslipidemia.² Second-generation antipsychotics are the biggest offenders, but taking a first-generation antipsychotic also can lead to these adverse effects.³

Most psychiatrists are aware of these risks and prefer that their patients do not experience them. However, many psychiatrists neglect proper monitoring or, like Dr. V, find it hard to ensure it happens and thus worry about clinical deterioration if patients stop taking an antipsychotic.⁴ If you are in the same situation as Dr. V, what medicolegal risks are you facing?

To answer this question, we will:

• review the clinical guidelines and standards for monitoring metabolic effects of antipsychotics
• examine how well (or poorly) physicians adhere to these standards
• discuss what “standard of care” means and how a practice guideline affects the standard effects
• propose how psychiatrists can do better at policing the metabolic effects of antipsychotics.

I’ll be watching you: Following guidelines
Several medical specialty societies have published guidelines for monitoring the metabolic effects of antipsychotics.^5-8 These guidelines instruct physicians to obtain a thorough personal and family history; consider metabolic risks when starting a medication; and monitor weight, waist circumference, blood pressure, glucose, hemoglobin A_1c, and lipids at various intervals. They also advise referral for management of detected metabolic problems.

Although the recommendations seem clear, many physicians don’t follow them. A 2012 meta-analysis of 48 studies, covering >200,000 antipsychotic-treated patients, showed that baseline measurements of cholesterol, glucose, and weight occurred in <50% of cases.⁹ A more recent review found that, among adults with a serious mental illness, the rate of lipid testing varied from 6% to 85% and for glucose monitoring, between 18% and 75%.¹⁰ In the first years after antipsychotic monitoring guidelines were established, they had only a modest impact on practice,^9,11 and some studies showed the guidelines made no difference at all.^12-14

Monitoring compliance varies with the type of insurance coverage patients have but remains suboptimal among the commercially insured,¹¹ Medicaid patients,^14-16 and veterans.^17,18 Studies on antipsychotic treatment in children, adolescents, patients with dementia, and patients with an intellectual disability show insufficient monitoring as well.^{9,14,17,19-21} The reasons for these gaps are manifold, but one commonly cited factor is uncertainty about whether the psychiatrist or primary care physician should handle monitoring.²²

Every claim you stake: The ‘standard of care’
In a medical malpractice case, the party claiming injury must show that the accused physician failed to follow “the generally recognized practices and procedures which would be exercised by ordinary competent practitioners in a defendant doctor’s field of medicine under the same or similar circumstances.”²³ In the studies mentioned above,^9-14 a large fraction of psychiatrists—many of whom, we can presume, are “competent practitioners”—don’t follow the antipsychotic monitoring guidelines in actual practice. Could failing to follow those guidelines still be the basis for a successful lawsuit?

The answer seems to be ‘yes.’ Published legal decisions describe malpractice lawsuits alleging physicians’ failure to follow antipsychotic guidelines,^24,25 and online advertisements show that attorneys believe such cases can generate a payout.^26,27 This may seem odd, given what studies say about psychiatrists’ monitoring practices. But determining the “standard of care” in a malpractice case is not an empirical question; it is a legal matter that is decided based on the testimony of expert witnesses.²⁸ Here, customary practice matters, but it’s not the whole story.

Although the standard of care against which courts measure a physician’s actions “is that of a reasonably prudent practitioner …, The degree of care actually practiced by members of the profession is only some evidence of what is reasonably prudent—it is not dispositive.”²⁹ To support their opinion concerning the standard of care, testifying medical witnesses sometimes use practice guidelines. In this case, an explanation of why a particular guideline was chosen is crucial.³⁰

Using guidelines to establish the standard is controversial. On one hand, using guidelines in malpractice litigation allows for some consistency about expectations of practitioners.^31,32 Although guidelines are not identical to evidenced-based medicine, they generally reflect an evidence-based expert consensus about sound medical practice. If a hospital uses a guideline to train its employees, the guideline provides the courts with clear information on what should have happened.^33,34 Laws in some states allow clinicians to invoke their adherence to a guideline in defense against malpractice claims.³⁵

On the other hand, critics contend that guidelines may not set an accurate standard for the quality of care, nor do they necessarily reflect a proper balance of the conflicting interests of patients and the health care system.³⁶ The American Psychiatric Association states that its practice guidelines “are not intended to serve or be construed as a ‘standard of medical care.’”³⁷

Conformity is not the only measure of prudent practice, and following guidelines does not immunize a clinician from lawsuit if a particular clinical situation demands a different course of action.³² Guidelines can be costly to implement,³⁶ compliance with guidelines generally is low,³⁵ and national guidelines do not necessarily improve the quality of care.³⁸ Last, relying on guidelines to determine the standard of care might stifle innovation or development of alternate approaches by silencing viewpoints.^39,40 Table 1^33-35,39,41 (page 60)summarizes variables that make a guideline more indicative of the standard of care.
 

Every step you take: Better monitoring
Medical professionals often are slow to update their practice to reflect new knowledge about optimal treatment. But practice guidelines influence the court’s views about the standard of care, and Dr. V’s question shows that he and his colleagues agree that metabolic status needs to be better monitored when patients take antipsychotic drugs. The following discussion and Table 2^42-45 offer suggestions for how psychiatrists and their practice settings could better accomplish this.

Electronic health records (EHRs). Monitor­ing health indices often is the largest hurdle that health care professionals face.⁴⁶ However, large health care systems with EHRs are in a good position to develop and implement automated computer routines that track which patients need monitoring and note due dates, abnormal results, and management interventions.⁴² Some studies suggest that monitoring rates in both inpatient⁴⁷ and outpatient⁴⁸ settings improve with built-in EHR reminders. However, if a system uses too many reminders, the resulting “alert fatigue” will limit their value.²² Providing individual feedback about monitoring practices may enhance physicians’ buy-in to reminder systems.⁴⁸
 

Integrated care systems can improve patient outcomes, particularly antipsychotic monitoring. Advantages include shared funding streams, a unified medical record, coordinated scheduling of psychiatric and primary care appointments, and addressing blood-draw refusals.⁴³ More frequent primary care visits make antipsychotic monitoring more likely.¹¹ Ultimately, integrated care could resolve problems related to determining which clinicians are responsible for monitoring and managing adverse metabolic effects.

Third-party payers. Managed care interventions also could improve monitoring rates.⁴⁴ Prior authorization often requires physicians to obtain appropriate lab work. Insurers might contact physicians with educational interventions, including free webinars, provider alerts, and letters about monitoring rates in their region. Some insurers also provide disease management programs for patients and their caregivers.

Individual and small group practices. Psychiatrists who practice outside a large health care system might designate 2 months each year as “physical health months.” In the “Let’s Get Physical” program,⁴⁵ physicians were given longer appointment times during these months to address metabolic monitoring, provide education about managing side effects of medication, and encourage better diets and exercise.

Overall, the best techniques might be those implicit to good doctoring: clear and open communication with patients, effective patient education, respect of informed consent, and thorough follow-up.⁴⁹

Dear Dr. Mossman,

All the psychiatrists at our clinic agree: It is hard to remember when our patients who take an antipsychotic are due for metabolic monitoring, and it’s even harder to get many of them to follow through with timely blood tests. For many, stopping their medication would be a bad idea. If we keep a patient on an antipsychotic and a metabolic problem results, how serious is our malpractice liability risk?

Submitted by “Dr. V”

Antipsychotics, the mainstay of treatment for schizophrenia,¹ put patients at risk of gaining weight and developing metabolic syndrome, including type 2 diabetes mellitus, hypertension, and dyslipidemia.² Second-generation antipsychotics are the biggest offenders, but taking a first-generation antipsychotic also can lead to these adverse effects.³

Most psychiatrists are aware of these risks and prefer that their patients do not experience them. However, many psychiatrists neglect proper monitoring or, like Dr. V, find it hard to ensure it happens and thus worry about clinical deterioration if patients stop taking an antipsychotic.⁴ If you are in the same situation as Dr. V, what medicolegal risks are you facing?

To answer this question, we will:

• review the clinical guidelines and standards for monitoring metabolic effects of antipsychotics
• examine how well (or poorly) physicians adhere to these standards
• discuss what “standard of care” means and how a practice guideline affects the standard effects
• propose how psychiatrists can do better at policing the metabolic effects of antipsychotics.

I’ll be watching you: Following guidelines
Several medical specialty societies have published guidelines for monitoring the metabolic effects of antipsychotics.^5-8 These guidelines instruct physicians to obtain a thorough personal and family history; consider metabolic risks when starting a medication; and monitor weight, waist circumference, blood pressure, glucose, hemoglobin A_1c, and lipids at various intervals. They also advise referral for management of detected metabolic problems.

Although the recommendations seem clear, many physicians don’t follow them. A 2012 meta-analysis of 48 studies, covering >200,000 antipsychotic-treated patients, showed that baseline measurements of cholesterol, glucose, and weight occurred in <50% of cases.⁹ A more recent review found that, among adults with a serious mental illness, the rate of lipid testing varied from 6% to 85% and for glucose monitoring, between 18% and 75%.¹⁰ In the first years after antipsychotic monitoring guidelines were established, they had only a modest impact on practice,^9,11 and some studies showed the guidelines made no difference at all.^12-14

Monitoring compliance varies with the type of insurance coverage patients have but remains suboptimal among the commercially insured,¹¹ Medicaid patients,^14-16 and veterans.^17,18 Studies on antipsychotic treatment in children, adolescents, patients with dementia, and patients with an intellectual disability show insufficient monitoring as well.^{9,14,17,19-21} The reasons for these gaps are manifold, but one commonly cited factor is uncertainty about whether the psychiatrist or primary care physician should handle monitoring.²²

Every claim you stake: The ‘standard of care’
In a medical malpractice case, the party claiming injury must show that the accused physician failed to follow “the generally recognized practices and procedures which would be exercised by ordinary competent practitioners in a defendant doctor’s field of medicine under the same or similar circumstances.”²³ In the studies mentioned above,^9-14 a large fraction of psychiatrists—many of whom, we can presume, are “competent practitioners”—don’t follow the antipsychotic monitoring guidelines in actual practice. Could failing to follow those guidelines still be the basis for a successful lawsuit?

The answer seems to be ‘yes.’ Published legal decisions describe malpractice lawsuits alleging physicians’ failure to follow antipsychotic guidelines,^24,25 and online advertisements show that attorneys believe such cases can generate a payout.^26,27 This may seem odd, given what studies say about psychiatrists’ monitoring practices. But determining the “standard of care” in a malpractice case is not an empirical question; it is a legal matter that is decided based on the testimony of expert witnesses.²⁸ Here, customary practice matters, but it’s not the whole story.

Although the standard of care against which courts measure a physician’s actions “is that of a reasonably prudent practitioner …, The degree of care actually practiced by members of the profession is only some evidence of what is reasonably prudent—it is not dispositive.”²⁹ To support their opinion concerning the standard of care, testifying medical witnesses sometimes use practice guidelines. In this case, an explanation of why a particular guideline was chosen is crucial.³⁰

Using guidelines to establish the standard is controversial. On one hand, using guidelines in malpractice litigation allows for some consistency about expectations of practitioners.^31,32 Although guidelines are not identical to evidenced-based medicine, they generally reflect an evidence-based expert consensus about sound medical practice. If a hospital uses a guideline to train its employees, the guideline provides the courts with clear information on what should have happened.^33,34 Laws in some states allow clinicians to invoke their adherence to a guideline in defense against malpractice claims.³⁵

On the other hand, critics contend that guidelines may not set an accurate standard for the quality of care, nor do they necessarily reflect a proper balance of the conflicting interests of patients and the health care system.³⁶ The American Psychiatric Association states that its practice guidelines “are not intended to serve or be construed as a ‘standard of medical care.’”³⁷

Conformity is not the only measure of prudent practice, and following guidelines does not immunize a clinician from lawsuit if a particular clinical situation demands a different course of action.³² Guidelines can be costly to implement,³⁶ compliance with guidelines generally is low,³⁵ and national guidelines do not necessarily improve the quality of care.³⁸ Last, relying on guidelines to determine the standard of care might stifle innovation or development of alternate approaches by silencing viewpoints.^39,40 Table 1^33-35,39,41 (page 60)summarizes variables that make a guideline more indicative of the standard of care.
 

Every step you take: Better monitoring
Medical professionals often are slow to update their practice to reflect new knowledge about optimal treatment. But practice guidelines influence the court’s views about the standard of care, and Dr. V’s question shows that he and his colleagues agree that metabolic status needs to be better monitored when patients take antipsychotic drugs. The following discussion and Table 2^42-45 offer suggestions for how psychiatrists and their practice settings could better accomplish this.

Electronic health records (EHRs). Monitor­ing health indices often is the largest hurdle that health care professionals face.⁴⁶ However, large health care systems with EHRs are in a good position to develop and implement automated computer routines that track which patients need monitoring and note due dates, abnormal results, and management interventions.⁴² Some studies suggest that monitoring rates in both inpatient⁴⁷ and outpatient⁴⁸ settings improve with built-in EHR reminders. However, if a system uses too many reminders, the resulting “alert fatigue” will limit their value.²² Providing individual feedback about monitoring practices may enhance physicians’ buy-in to reminder systems.⁴⁸
 

Integrated care systems can improve patient outcomes, particularly antipsychotic monitoring. Advantages include shared funding streams, a unified medical record, coordinated scheduling of psychiatric and primary care appointments, and addressing blood-draw refusals.⁴³ More frequent primary care visits make antipsychotic monitoring more likely.¹¹ Ultimately, integrated care could resolve problems related to determining which clinicians are responsible for monitoring and managing adverse metabolic effects.

Third-party payers. Managed care interventions also could improve monitoring rates.⁴⁴ Prior authorization often requires physicians to obtain appropriate lab work. Insurers might contact physicians with educational interventions, including free webinars, provider alerts, and letters about monitoring rates in their region. Some insurers also provide disease management programs for patients and their caregivers.

Individual and small group practices. Psychiatrists who practice outside a large health care system might designate 2 months each year as “physical health months.” In the “Let’s Get Physical” program,⁴⁵ physicians were given longer appointment times during these months to address metabolic monitoring, provide education about managing side effects of medication, and encourage better diets and exercise.

Overall, the best techniques might be those implicit to good doctoring: clear and open communication with patients, effective patient education, respect of informed consent, and thorough follow-up.⁴⁹

Since 2008, the FDA has cleared 4 transcranial magnetic stimulation (TMS) devices for treating depression (Related Resources). In that time, the availability of TMS has steadily grown within and outside the United States.

Parallel with increasing clinical utilization of this technology, research continues into the benefit of TMS for treatment-resistant depression; such research includes additional, supportive, acute, sham-controlled trials; comparison trials with electroconvulsive therapy (ECT) for more severe episodes of depression; short- and long-term real-world outcome studies; exploration of alternative treatment parameters to further enhance its efficacy; and the development of other TMS approaches. In this article, we review recent developments in the application of TMS to treat major depressive disorder—in particular, treatment-resistant depression (Box).
 

Therapeutic neuromodulation
The underlying premise of neuromodulation is that the brain is an electrochemical organ that can be modulated by pharmacotherapy or device-based approaches, or their combination.¹ ECT is the prototypic device-based neuromodulation approach, and remains one of the most effective treatments for severe depression.

More recently, however, other methods have been, and continue to be, developed to treat patients who do not achieve adequate benefit from psychotherapy or medical therapy, or both, and who might not be an ideal candidate for ECT (Table,¹). In addition to the potential therapeutic benefit of these alternative strategies, some could avoid safety and tolerability concerns associated with medication (weight gain, sexual dysfunction) and ECT (eg, cognitive deficits).

TMS, which utilizes intense, localized magnetic fields to alter activity in neural circuits implicated in the pathophysiology of depression, represents an important example of this initiative.²

TMS has established efficacy for depression
Sham-controlled trials. Several randomized, sham-controlled acute trials have demonstrated the efficacy of TMS for treatment-resistant depression.

A recent meta-analysis considered 18 studies (N = 1,970) that met the authors’ criteria for inclusion.³ They found that TMS monotherapy was statistically and clinically more effective than a sham procedure based on:

• improvement in depressive symptoms (mean decrease in baseline Hamilton Depression Rating Scale [HDRS] score, −4.53 [95% CI, −6.11 to −2.96])
• response rate; response was 3 times more likely with TMS (relative risk 3.38 [95% CI, 2.24 to 5.10])
• remission rate; remission was 5 times more likely with TMS (relative risk, 5.07 [95% CI, 2.50 to 10.30]).

Another meta-analysis (7 studies, N = 279) considered TMS as an augmentation strategy to standard medication for treatment-resistant depression.⁴ The authors reported that, based on change in HDRS scores, the pooled standardized mean difference between active and sham TMS augmentation was 0.86 (P < .00001). Furthermore, the pooled response rate with TMS augmentation was 46.6%, compared with 22.1% with the sham procedure (P < .0003).

Acute naturalistic TMS studies. The efficacy of TMS is supported by a large, naturalistic study of 307 patients with treatment-resistant depression who were assessed at baseline and during a standard course of TMS.⁵ Considering change score in the Clinician Global Impressions-Severity (CGI-S) scale, significant improvement was seen from baseline to end of treatment (−1.9 ± 1.4; P < .0001), with a clinician-assessed response rate of 58.0% and remission rate of 37.1%. Of note: Self-reported quality-of-life measures (on the Medical Outcomes Study 36-Item Short-Form Health Survey and EuroQol 5-Dimensions) also significantly improved during this relatively brief period.⁶

Maintenance strategies after acute TMS response. Most patients referred for TMS have a depressive illness characterized by a chronic, relapsing course and inadequate response to pharmacotherapy or psychotherapy, or their combination. An effective maintenance strategy after acute response to TMS is paramount. This includes:

• prolonged tapering schedule after an acute TMS course is completed
• maintenance medication or psychotherapy, or both
• scheduled periodic maintenance TMS sessions (usually as an augmentation strategy)
• reintroduction of TMS as needed with early signs of relapse. In this context, several trials have assessed the durability of acute TMS benefit.

A semi-controlled maintenance study followed 99 patients who had at least a 25% decrease in baseline HDRS score after acute TMS treatment.⁷ They were then tapered from their TMS sessions over 3 weeks while an antidepressant was titrated up. If, at any time during the subsequent 6 months, early signs of depression relapse were noted (ie, change of at least 1 point on the CGI-S for 2 consecutive weeks), TMS was reintroduced. At the end of the trial, 10 patients (13%) had relapsed and 38 (38%) had an exacerbation of symptoms sufficient to warrant reintroduction of TMS. Of those, 32 (84%) re-achieved mood stability.

In another study, 50 patients who had achieved remission during an acute course of TMS were followed for 3 months.⁸ After TMS taper and continued pharmacotherapy or naturalistic follow-up, 29 (58%) remained in remission; 2 (4%) maintained partial response; and 1 (2%) relapsed.

In a controlled, pilot, maintenance trial, 67 unmedicated patients with treatment-resistant depression received an acute course of TMS.⁹ Forty-seven of the responders were then randomized to a 1-year follow-up trial with or without a scheduled monthly TMS session. All patients could receive reintroduction TMS if they met criteria for symptom worsening.

Both groups had a similar outcome. The number of patients who did not require TMS reintroduction was 9 of 23 (39%) in the scheduled TMS group vs 9 of 26 (35%) in the no-scheduled TMS group (P < .1). Although no difference was noted between groups, the authors commented that these preliminary results will help inform larger, more definitive trials. They concluded that both acute and maintenance TMS monotherapy might be an option—for some patients.

A long-term, naturalistic outcomes study followed 257 treatment-resistant depressed patients for 1 year after they responded to an acute course of TMS.¹⁰ In addition to most patients receiving ongoing maintenance medication, they also could receive reintroduction of TMS if symptoms became worse.

Compared with pre-TMS baseline, there was a statistically significant reduction in the mean total score on the CGI-S scale (primary outcome, P < .0001) at the end of acute treatment that was sustained at follow-up. Ninety-six patients (36.2%) required reintroduction of TMS and 75 of 120 (62.5%) who initially met response or remission criteria after acute treatment continued to meet response criteria after 1 year. The authors concluded that TMS demonstrated both a statistically and clinically meaningful durability of acute benefit during this time frame.

TMS and electroconvulsive therapy
For more than 75 years, ECT has consistently proved to be an effective treatment for major depressive disorder. Although the use of ECT has fluctuated over this period, one practice survey estimated that 100,000 patients receive ECT annually.¹¹

ECT has limitations, however, including cost, the need for general anesthesia, and cognitive deficits that range from short-term confusion to anterograde and retrograde amnesia, which can persist for weeks beyond active treatment.¹² Despite increasing awareness of mental illness, stigma also remains a significant barrier to receiving ECT.

TMS vs ECT. Several trials have directly compared ECT and TMS:

• A recent meta-analysis of 9 trials included 384 patients with depression who were considered clinically appropriate for ECT and were randomized to one or the other treatment.¹³ Both modalities produced a significant reduction in baseline HDRS score, but ECT (15.4 point reduction) was superior to TMS (9.3 point reduction) in the degree of improvement (P < .01).
• Another meta-analysis of 9 trials (N = 425) found ECT superior to TMS in terms of response (P < .03) and remission (P < .006) rates, based on improvement in the HDRS score.¹⁴ When psychotic depressed patients were excluded, however, TMS produced effects equivalent to ECT.

In contrast to what was seen with ECT, cognitive testing of patients who received TMS revealed no deterioration in any domain. Furthermore, one of the comparison studies observed a modest, but statistically significant, improvement in patient’s working memory-executive function, objective memory, and fine-motor speed over the course of TMS treatment.¹⁵

TMS plus ECT. A 2-week, randomized, single-blind, controlled pilot study (N = 22) examined the combination of TMS and ECT as acute treatment of depression.¹⁶ Patients were assigned to receive either unilateral non-dominant (UND) ECT 3 days a week or a combination of 1 UND ECT treatment followed by 4 days of TMS. At the conclusion of treatment, UND ECT plus TMS group produced comparable efficacy and fewer adverse effects compared with the UND ECT-only group.

TMS maintenance after acute ECT response. Most patients who are referred for ECT have a depressive illness characterized by repeated episodes and incomplete response to pharmacotherapy or psychotherapy, or both. The need for an effective maintenance strategy after the acute response is therefore critical. Medication or ECT, or both, are commonly used to maintain acute benefit but, regrettably, a recent systematic review of the durability of benefit with such strategies found a substantial percentage (approximately 50%) of patients relapsed within the first year.¹⁷

• In this context, a case series report found that 1 or 2 weekly, sequential, bilateral TMS treatments after a successful acute course of ECT maintained response in 5 of 6 patients over 6 to 12 months.¹⁸
• Another case series (N = 6) transitioned stable patients from maintenance ECT to maintenance TMS, primarily because of adverse effects with ECT.¹⁹ With a mean frequency of 1 TMS treatment every 3.5 weeks, all 6 patients remained stable for as long as 6 months. Subsequently, 2 patients relapsed—1 at 8 months and 1 at 9 months.

Advantages of maintenance TMS over maintenance ECT include lower cost, fewer adverse effects (particularly cognitive deficits), and the ability to remain independent during the period of the treatment sessions.

TMS as an assessment tool for ECT response. TMS can be used to study excitability in cortical circuits. In a study, EEG potentials evoked by TMS before and after a course of ECT in 8 severely depressed patients revealed an increase in frontal cortical excitability, compared with baseline.²⁰ Such findings support the ability of ECT to produce synaptic potentiation in humans. Furthermore, to the extent that depression presents with alterations in frontal cortical excitability, serial EEG-TMS measurements might be an effective tool to guide and monitor treatment progress with ECT, as well as other forms of therapeutic modulation.

Summing up: TMS and ECT. Although a definitive comparative study is needed, available evidence suggests that TMS might be an alternative treatment in a subgroup of patients who are referred for ECT. Factors that might warrant considering TMS over ECT include:

• patient preference
• fear of anesthesia
• concern about cognitive deficits
• stigma.

Although TMS might offer a workable alternative to ECT for acute and maintenance treatment of depression in selected patients, further refinement of the delivery of TMS is also needed to (1) enhance its efficacy and (2) identify clinical and biological markers to better define this select population.

Standard TMS treatment parameters
Superficial TMS. Superficial TMS for depression typically involves a single coil placed over the left dorsolateral prefrontal cortex. The standard, FDA-approved protocol includes stimulating at 110% of motor threshold with 75, 4-second trains at 10 Hz (ie, 40 stimulations) interspersed by 26-second intertrain intervals. Without interruption, a standard treatment session takes 37.5 minutes and delivers a total of 3,000 pulses. Most patients require 20 to 30 sessions, on a Monday-through-Friday schedule, to achieve optimal benefit.

This approach stimulates to a depth of approximately 2 or 3 cm. The coil usually is placed over the left dorsolateral prefrontal cortex because earlier studies indicated that decreased activity in this part of the brain correlates with symptoms of depression. When TMS is administered in a rapid repetitive fashion (at >1 Hz; typically, at 10 Hz), blood flow and metabolism in that area of the brain are increased. In addition, imaging studies indicate that trans-synaptic connections with deeper parts of the brain also allow modulation of other relevant neural circuits.

An alternate approach, less well-studied, involves low-frequency stimulation over the right dorsolateral prefrontal cortex. Parameters differ from what is used in left high-frequency dorsolateral prefrontal cortex TMS: frequency <1 Hz; train durations as long as 15 minutes; an intertrain interval of 25 to 180 seconds; 120 to 900 stimulations per train; and 2,400 to 18,000 total stimulations.

One hypothesis is that this low-frequency approach selectively stimulates inhibitory interneurons, decreases local neuronal activity and diminishes blood flow to deeper structures, such as the amygdala. Although right low-frequency TMS, compared with left high-frequency TMS, has potential advantages of better tolerability and decreased risk for seizures, its relative efficacy is unclear.

Deep TMS. Studies also are pursuing different coil configurations that allow for more direct stimulation of relevant structures (eg, prefrontal neuronal pathways associated with the reward system).

One of these coil designs (ie, the H-coil), coupled to a Magstim TMS stimulator, recently received FDA clearance for treatment-resistant depression. In the pivotal, sham-controlled study, patients received 20 treatment sessions over 4 weeks.²¹ The treatment protocol consisted of a helmet-like coil placed over the medial and lateral prefrontal cortex. Stimulation parameters included an 18-Hz frequency; stimulation intensity of 120% motor threshold; stimulation train duration of 2 seconds; and an intertrain interval of 20 seconds. The treatment sessions lasted 20.2 minutes and delivered a total of 1,980 stimulations.

Based on the 21-item HDRS, the active treatment coil group achieved a significantly greater decrease in baseline score (6.39 vs 3.28; P < .008); a greater response rate (37% vs 27.8%; P < .03); and a greater remission rate (30.4% vs 15.8%; P < .016) compared with the sham coil group.

Next, in what is the only randomized, controlled maintenance assessment to date, the same patients were followed for an additional 12 weeks, continuing blinded treatments twice weekly. At the end of the second phase, the active treatment group also demonstrated greater benefit than the sham group (P < .03). One seizure did occur, possibly related to excessive alcohol use; but this raises the question of whether treating at a higher frequency (18 Hz) with greater depth and less focality might increase the risk of seizure.

To assess the potential advantages, as well as the relative safety, of this approach over standard TMS delivery, an adequately designed and powered trial comparing the H-coil and a single-coil device is needed.

Alternate TMS approaches
Efforts to improve the clinical effectiveness of TMS for treating depression include several approaches.

Theta burst stimulation (TBS) is a patterned form of TMS pulse delivery that utilizes high and low frequencies in the same stimulus train (eg, three 50-Hz bursts delivered 5 times a second). Such a pulse sequence can modulate long-term depression and long-term potentiation mechanisms that induce plasticity in areas such as the hippocampus.²²

Intermittent TBS (iTBS) administers stimulations over a relatively brief duration (eg, 2 seconds) or intermittently (eg, every 10 seconds) for a specific period (eg, 190 seconds [600 pulses in total]) over the left dorsolateral prefrontal cortex. This technique induces long-term potentiation and produces effects similar to those of high-frequency TMS.

In contrast, continuous TBS (cTBS) administers a continuous train (eg, 40 seconds [600 total pulses]) over the right dorsolateral prefrontal cortex. This induces long-term depression and produces effects similar to low-frequency TMS.

Recent studies using different delivery paradigms have generated mixed results:

Study 1: Fifty-six patients with depression received active treatment; 17 others, a sham procedure.²³ This study used 3 different conditions:

• a combination of low-frequency and high-frequency TMS stimulation, administered over the right and left dorsolateral prefrontal cortices, respectively
• a combination of iTBS over the left dorsolateral prefrontal cortex and cTBS over the right dorsolateral prefrontal cortex
• a sham procedure, in which no magnetic field was created.

Neither active treatment arm separated from the sham procedure based on change scores in the 21-item HDRS (P = not significant).

Study 2: Sixty treatment-resistant depression patients were assigned to cTBS, iTBS, a combination of the 2 procedures, or a sham procedure.²⁴ After 2 weeks, the active treatment arms produced the greatest benefit, based on change in scores on the 17-item HDRS, which differed significantly among the 4 groups (F value = 6.166; P < .001); the iTBS and combination arms demonstrated the most robust effect.

There were also significantly more responders in the iTBS (40.0%) and combination groups (66.7%) than in the cTBS (25.0%) and sham groups (13.3%) (P < .010). A lower level of treatment refractoriness predicted a better outcome.

Study 3: Twenty-nine depressed patients were randomized to cTBS over the right dorsolateral prefrontal cortex or a sham procedure.²⁵ Overall, there was no difference between groups; however, actively treated patients who were unmedicated (n = 3) or remained on a stable dosage of medication during treatment (n = 8) did experience a significantly greater reduction in the HDRS score.

Study 4: In a pilot trial, 32 depressed patients were randomized to 30 sessions of adjunctive combined iTBS plus cTBS or bilateral sham TBS.²⁶ Based on reduction from the baseline Montgomery-Åsberg Depression Rating Scale score, 9 patients in the active treatment group and 4 in the sham group achieved response (odds ratio, 3.86; P < .048).

If at least comparable efficacy can be clearly demonstrated, advantages of TBS over standard TMS include a significantly reduced administration time, which might allow for more patients to be treated and reduce associated costs of treatment.²⁷

Magnetic low-field synchronized stimulation is produced by rotating spherical rare-earth magnets that are synchronized to an individual’s alpha frequency. A recent 6-week, double-blind, sham-controlled trial (N = 202) reported that, in the intention-to-treat population, there was no difference in outcome between treatment arms. In patients who completed the study according to protocol (120 of 202), however, active treatment was significantly better in decreasing baseline HDRS score (P < .033).²⁸

Magnetic seizure therapy (MST) is an experimental approach to treating patients with more severe depression that is resistant to medical therapy. The primary aim is to use TMS to induce a seizure, thus achieving the same efficacy as provided by ECT but without the adverse cognitive effects of ECT. With MST, the TMS device uses much higher stimulation settings to produce a seizure—the goal being to avoid direct electrical current to the brain’s memory centers.²⁹

A pilot study considered the clinical and cognitive effects of MST in a group of 26 treatment-resistant depression patients (10 randomized; 16 open-label).³⁰ Based on reduction in baseline HDRS scores at the end of the trial, 69% of patients achieved response and 46% met remission criteria; however, one-half of patients relapsed within 6 months.

Importantly, no cognitive adverse effects were observed. Furthermore, the antidepressant and anti-anxiety effects of MST were associated with localized metabolic changes in brain areas implicated in the pathophysiology of depression.

The investigators concluded that MST might constitute an effective, well-tolerated, and safe treatment for patients unable to benefit from available medical therapies for depression. In addition to confirmation of acute benefit in more definitive trials, the issue of durability of effect needs further clarification.

TMS is a key component of neuropsychiatric practice
It has been 3 decades since Barker et al³¹ developed the technology to deliver intense, localized magnetic pulses to specific areas of the nervous system. During this period, the role of TMS as a probe of the central and peripheral nervous systems has expanded to include various therapeutic applications, primarily focusing on treatment-resistant major depressive disorder.

Now, increasing sophistication in the choice of stimulation parameters and other ongoing efforts to optimize the benefits of TMS are yielding improved clinical outcomes. Research is still needed to better define the place of TMS in the management of subtypes of depression that are particularly difficult to treat and that do not benefit adequately from medications or psychotherapy or their combination.

Growing support from controlled trials, systematic reviews, meta-analyses, naturalistic outcome studies, and professional guidelines indicate that TMS has an increasingly important role in clinical practice.

Since 2008, the FDA has cleared 4 transcranial magnetic stimulation (TMS) devices for treating depression (Related Resources). In that time, the availability of TMS has steadily grown within and outside the United States.

Parallel with increasing clinical utilization of this technology, research continues into the benefit of TMS for treatment-resistant depression; such research includes additional, supportive, acute, sham-controlled trials; comparison trials with electroconvulsive therapy (ECT) for more severe episodes of depression; short- and long-term real-world outcome studies; exploration of alternative treatment parameters to further enhance its efficacy; and the development of other TMS approaches. In this article, we review recent developments in the application of TMS to treat major depressive disorder—in particular, treatment-resistant depression (Box).
 

Therapeutic neuromodulation
The underlying premise of neuromodulation is that the brain is an electrochemical organ that can be modulated by pharmacotherapy or device-based approaches, or their combination.¹ ECT is the prototypic device-based neuromodulation approach, and remains one of the most effective treatments for severe depression.

More recently, however, other methods have been, and continue to be, developed to treat patients who do not achieve adequate benefit from psychotherapy or medical therapy, or both, and who might not be an ideal candidate for ECT (Table,¹). In addition to the potential therapeutic benefit of these alternative strategies, some could avoid safety and tolerability concerns associated with medication (weight gain, sexual dysfunction) and ECT (eg, cognitive deficits).

TMS, which utilizes intense, localized magnetic fields to alter activity in neural circuits implicated in the pathophysiology of depression, represents an important example of this initiative.²

TMS has established efficacy for depression
Sham-controlled trials. Several randomized, sham-controlled acute trials have demonstrated the efficacy of TMS for treatment-resistant depression.

A recent meta-analysis considered 18 studies (N = 1,970) that met the authors’ criteria for inclusion.³ They found that TMS monotherapy was statistically and clinically more effective than a sham procedure based on:

• improvement in depressive symptoms (mean decrease in baseline Hamilton Depression Rating Scale [HDRS] score, −4.53 [95% CI, −6.11 to −2.96])
• response rate; response was 3 times more likely with TMS (relative risk 3.38 [95% CI, 2.24 to 5.10])
• remission rate; remission was 5 times more likely with TMS (relative risk, 5.07 [95% CI, 2.50 to 10.30]).

Another meta-analysis (7 studies, N = 279) considered TMS as an augmentation strategy to standard medication for treatment-resistant depression.⁴ The authors reported that, based on change in HDRS scores, the pooled standardized mean difference between active and sham TMS augmentation was 0.86 (P < .00001). Furthermore, the pooled response rate with TMS augmentation was 46.6%, compared with 22.1% with the sham procedure (P < .0003).

Acute naturalistic TMS studies. The efficacy of TMS is supported by a large, naturalistic study of 307 patients with treatment-resistant depression who were assessed at baseline and during a standard course of TMS.⁵ Considering change score in the Clinician Global Impressions-Severity (CGI-S) scale, significant improvement was seen from baseline to end of treatment (−1.9 ± 1.4; P < .0001), with a clinician-assessed response rate of 58.0% and remission rate of 37.1%. Of note: Self-reported quality-of-life measures (on the Medical Outcomes Study 36-Item Short-Form Health Survey and EuroQol 5-Dimensions) also significantly improved during this relatively brief period.⁶

Maintenance strategies after acute TMS response. Most patients referred for TMS have a depressive illness characterized by a chronic, relapsing course and inadequate response to pharmacotherapy or psychotherapy, or their combination. An effective maintenance strategy after acute response to TMS is paramount. This includes:

• prolonged tapering schedule after an acute TMS course is completed
• maintenance medication or psychotherapy, or both
• scheduled periodic maintenance TMS sessions (usually as an augmentation strategy)
• reintroduction of TMS as needed with early signs of relapse. In this context, several trials have assessed the durability of acute TMS benefit.

A semi-controlled maintenance study followed 99 patients who had at least a 25% decrease in baseline HDRS score after acute TMS treatment.⁷ They were then tapered from their TMS sessions over 3 weeks while an antidepressant was titrated up. If, at any time during the subsequent 6 months, early signs of depression relapse were noted (ie, change of at least 1 point on the CGI-S for 2 consecutive weeks), TMS was reintroduced. At the end of the trial, 10 patients (13%) had relapsed and 38 (38%) had an exacerbation of symptoms sufficient to warrant reintroduction of TMS. Of those, 32 (84%) re-achieved mood stability.

In another study, 50 patients who had achieved remission during an acute course of TMS were followed for 3 months.⁸ After TMS taper and continued pharmacotherapy or naturalistic follow-up, 29 (58%) remained in remission; 2 (4%) maintained partial response; and 1 (2%) relapsed.

In a controlled, pilot, maintenance trial, 67 unmedicated patients with treatment-resistant depression received an acute course of TMS.⁹ Forty-seven of the responders were then randomized to a 1-year follow-up trial with or without a scheduled monthly TMS session. All patients could receive reintroduction TMS if they met criteria for symptom worsening.

Both groups had a similar outcome. The number of patients who did not require TMS reintroduction was 9 of 23 (39%) in the scheduled TMS group vs 9 of 26 (35%) in the no-scheduled TMS group (P < .1). Although no difference was noted between groups, the authors commented that these preliminary results will help inform larger, more definitive trials. They concluded that both acute and maintenance TMS monotherapy might be an option—for some patients.

A long-term, naturalistic outcomes study followed 257 treatment-resistant depressed patients for 1 year after they responded to an acute course of TMS.¹⁰ In addition to most patients receiving ongoing maintenance medication, they also could receive reintroduction of TMS if symptoms became worse.

Compared with pre-TMS baseline, there was a statistically significant reduction in the mean total score on the CGI-S scale (primary outcome, P < .0001) at the end of acute treatment that was sustained at follow-up. Ninety-six patients (36.2%) required reintroduction of TMS and 75 of 120 (62.5%) who initially met response or remission criteria after acute treatment continued to meet response criteria after 1 year. The authors concluded that TMS demonstrated both a statistically and clinically meaningful durability of acute benefit during this time frame.

TMS and electroconvulsive therapy
For more than 75 years, ECT has consistently proved to be an effective treatment for major depressive disorder. Although the use of ECT has fluctuated over this period, one practice survey estimated that 100,000 patients receive ECT annually.¹¹

ECT has limitations, however, including cost, the need for general anesthesia, and cognitive deficits that range from short-term confusion to anterograde and retrograde amnesia, which can persist for weeks beyond active treatment.¹² Despite increasing awareness of mental illness, stigma also remains a significant barrier to receiving ECT.

TMS vs ECT. Several trials have directly compared ECT and TMS:

• A recent meta-analysis of 9 trials included 384 patients with depression who were considered clinically appropriate for ECT and were randomized to one or the other treatment.¹³ Both modalities produced a significant reduction in baseline HDRS score, but ECT (15.4 point reduction) was superior to TMS (9.3 point reduction) in the degree of improvement (P < .01).
• Another meta-analysis of 9 trials (N = 425) found ECT superior to TMS in terms of response (P < .03) and remission (P < .006) rates, based on improvement in the HDRS score.¹⁴ When psychotic depressed patients were excluded, however, TMS produced effects equivalent to ECT.

In contrast to what was seen with ECT, cognitive testing of patients who received TMS revealed no deterioration in any domain. Furthermore, one of the comparison studies observed a modest, but statistically significant, improvement in patient’s working memory-executive function, objective memory, and fine-motor speed over the course of TMS treatment.¹⁵

TMS plus ECT. A 2-week, randomized, single-blind, controlled pilot study (N = 22) examined the combination of TMS and ECT as acute treatment of depression.¹⁶ Patients were assigned to receive either unilateral non-dominant (UND) ECT 3 days a week or a combination of 1 UND ECT treatment followed by 4 days of TMS. At the conclusion of treatment, UND ECT plus TMS group produced comparable efficacy and fewer adverse effects compared with the UND ECT-only group.

TMS maintenance after acute ECT response. Most patients who are referred for ECT have a depressive illness characterized by repeated episodes and incomplete response to pharmacotherapy or psychotherapy, or both. The need for an effective maintenance strategy after the acute response is therefore critical. Medication or ECT, or both, are commonly used to maintain acute benefit but, regrettably, a recent systematic review of the durability of benefit with such strategies found a substantial percentage (approximately 50%) of patients relapsed within the first year.¹⁷

• In this context, a case series report found that 1 or 2 weekly, sequential, bilateral TMS treatments after a successful acute course of ECT maintained response in 5 of 6 patients over 6 to 12 months.¹⁸
• Another case series (N = 6) transitioned stable patients from maintenance ECT to maintenance TMS, primarily because of adverse effects with ECT.¹⁹ With a mean frequency of 1 TMS treatment every 3.5 weeks, all 6 patients remained stable for as long as 6 months. Subsequently, 2 patients relapsed—1 at 8 months and 1 at 9 months.

Advantages of maintenance TMS over maintenance ECT include lower cost, fewer adverse effects (particularly cognitive deficits), and the ability to remain independent during the period of the treatment sessions.

TMS as an assessment tool for ECT response. TMS can be used to study excitability in cortical circuits. In a study, EEG potentials evoked by TMS before and after a course of ECT in 8 severely depressed patients revealed an increase in frontal cortical excitability, compared with baseline.²⁰ Such findings support the ability of ECT to produce synaptic potentiation in humans. Furthermore, to the extent that depression presents with alterations in frontal cortical excitability, serial EEG-TMS measurements might be an effective tool to guide and monitor treatment progress with ECT, as well as other forms of therapeutic modulation.

Summing up: TMS and ECT. Although a definitive comparative study is needed, available evidence suggests that TMS might be an alternative treatment in a subgroup of patients who are referred for ECT. Factors that might warrant considering TMS over ECT include:

• patient preference
• fear of anesthesia
• concern about cognitive deficits
• stigma.

Although TMS might offer a workable alternative to ECT for acute and maintenance treatment of depression in selected patients, further refinement of the delivery of TMS is also needed to (1) enhance its efficacy and (2) identify clinical and biological markers to better define this select population.

Standard TMS treatment parameters
Superficial TMS. Superficial TMS for depression typically involves a single coil placed over the left dorsolateral prefrontal cortex. The standard, FDA-approved protocol includes stimulating at 110% of motor threshold with 75, 4-second trains at 10 Hz (ie, 40 stimulations) interspersed by 26-second intertrain intervals. Without interruption, a standard treatment session takes 37.5 minutes and delivers a total of 3,000 pulses. Most patients require 20 to 30 sessions, on a Monday-through-Friday schedule, to achieve optimal benefit.

This approach stimulates to a depth of approximately 2 or 3 cm. The coil usually is placed over the left dorsolateral prefrontal cortex because earlier studies indicated that decreased activity in this part of the brain correlates with symptoms of depression. When TMS is administered in a rapid repetitive fashion (at >1 Hz; typically, at 10 Hz), blood flow and metabolism in that area of the brain are increased. In addition, imaging studies indicate that trans-synaptic connections with deeper parts of the brain also allow modulation of other relevant neural circuits.

An alternate approach, less well-studied, involves low-frequency stimulation over the right dorsolateral prefrontal cortex. Parameters differ from what is used in left high-frequency dorsolateral prefrontal cortex TMS: frequency <1 Hz; train durations as long as 15 minutes; an intertrain interval of 25 to 180 seconds; 120 to 900 stimulations per train; and 2,400 to 18,000 total stimulations.

One hypothesis is that this low-frequency approach selectively stimulates inhibitory interneurons, decreases local neuronal activity and diminishes blood flow to deeper structures, such as the amygdala. Although right low-frequency TMS, compared with left high-frequency TMS, has potential advantages of better tolerability and decreased risk for seizures, its relative efficacy is unclear.

Deep TMS. Studies also are pursuing different coil configurations that allow for more direct stimulation of relevant structures (eg, prefrontal neuronal pathways associated with the reward system).

One of these coil designs (ie, the H-coil), coupled to a Magstim TMS stimulator, recently received FDA clearance for treatment-resistant depression. In the pivotal, sham-controlled study, patients received 20 treatment sessions over 4 weeks.²¹ The treatment protocol consisted of a helmet-like coil placed over the medial and lateral prefrontal cortex. Stimulation parameters included an 18-Hz frequency; stimulation intensity of 120% motor threshold; stimulation train duration of 2 seconds; and an intertrain interval of 20 seconds. The treatment sessions lasted 20.2 minutes and delivered a total of 1,980 stimulations.

Based on the 21-item HDRS, the active treatment coil group achieved a significantly greater decrease in baseline score (6.39 vs 3.28; P < .008); a greater response rate (37% vs 27.8%; P < .03); and a greater remission rate (30.4% vs 15.8%; P < .016) compared with the sham coil group.

Next, in what is the only randomized, controlled maintenance assessment to date, the same patients were followed for an additional 12 weeks, continuing blinded treatments twice weekly. At the end of the second phase, the active treatment group also demonstrated greater benefit than the sham group (P < .03). One seizure did occur, possibly related to excessive alcohol use; but this raises the question of whether treating at a higher frequency (18 Hz) with greater depth and less focality might increase the risk of seizure.

To assess the potential advantages, as well as the relative safety, of this approach over standard TMS delivery, an adequately designed and powered trial comparing the H-coil and a single-coil device is needed.

Alternate TMS approaches
Efforts to improve the clinical effectiveness of TMS for treating depression include several approaches.

Theta burst stimulation (TBS) is a patterned form of TMS pulse delivery that utilizes high and low frequencies in the same stimulus train (eg, three 50-Hz bursts delivered 5 times a second). Such a pulse sequence can modulate long-term depression and long-term potentiation mechanisms that induce plasticity in areas such as the hippocampus.²²

Intermittent TBS (iTBS) administers stimulations over a relatively brief duration (eg, 2 seconds) or intermittently (eg, every 10 seconds) for a specific period (eg, 190 seconds [600 pulses in total]) over the left dorsolateral prefrontal cortex. This technique induces long-term potentiation and produces effects similar to those of high-frequency TMS.

In contrast, continuous TBS (cTBS) administers a continuous train (eg, 40 seconds [600 total pulses]) over the right dorsolateral prefrontal cortex. This induces long-term depression and produces effects similar to low-frequency TMS.

Recent studies using different delivery paradigms have generated mixed results:

Study 1: Fifty-six patients with depression received active treatment; 17 others, a sham procedure.²³ This study used 3 different conditions:

• a combination of low-frequency and high-frequency TMS stimulation, administered over the right and left dorsolateral prefrontal cortices, respectively
• a combination of iTBS over the left dorsolateral prefrontal cortex and cTBS over the right dorsolateral prefrontal cortex
• a sham procedure, in which no magnetic field was created.

Neither active treatment arm separated from the sham procedure based on change scores in the 21-item HDRS (P = not significant).

Study 2: Sixty treatment-resistant depression patients were assigned to cTBS, iTBS, a combination of the 2 procedures, or a sham procedure.²⁴ After 2 weeks, the active treatment arms produced the greatest benefit, based on change in scores on the 17-item HDRS, which differed significantly among the 4 groups (F value = 6.166; P < .001); the iTBS and combination arms demonstrated the most robust effect.

There were also significantly more responders in the iTBS (40.0%) and combination groups (66.7%) than in the cTBS (25.0%) and sham groups (13.3%) (P < .010). A lower level of treatment refractoriness predicted a better outcome.

Study 3: Twenty-nine depressed patients were randomized to cTBS over the right dorsolateral prefrontal cortex or a sham procedure.²⁵ Overall, there was no difference between groups; however, actively treated patients who were unmedicated (n = 3) or remained on a stable dosage of medication during treatment (n = 8) did experience a significantly greater reduction in the HDRS score.

Study 4: In a pilot trial, 32 depressed patients were randomized to 30 sessions of adjunctive combined iTBS plus cTBS or bilateral sham TBS.²⁶ Based on reduction from the baseline Montgomery-Åsberg Depression Rating Scale score, 9 patients in the active treatment group and 4 in the sham group achieved response (odds ratio, 3.86; P < .048).

If at least comparable efficacy can be clearly demonstrated, advantages of TBS over standard TMS include a significantly reduced administration time, which might allow for more patients to be treated and reduce associated costs of treatment.²⁷

Magnetic low-field synchronized stimulation is produced by rotating spherical rare-earth magnets that are synchronized to an individual’s alpha frequency. A recent 6-week, double-blind, sham-controlled trial (N = 202) reported that, in the intention-to-treat population, there was no difference in outcome between treatment arms. In patients who completed the study according to protocol (120 of 202), however, active treatment was significantly better in decreasing baseline HDRS score (P < .033).²⁸

Magnetic seizure therapy (MST) is an experimental approach to treating patients with more severe depression that is resistant to medical therapy. The primary aim is to use TMS to induce a seizure, thus achieving the same efficacy as provided by ECT but without the adverse cognitive effects of ECT. With MST, the TMS device uses much higher stimulation settings to produce a seizure—the goal being to avoid direct electrical current to the brain’s memory centers.²⁹

A pilot study considered the clinical and cognitive effects of MST in a group of 26 treatment-resistant depression patients (10 randomized; 16 open-label).³⁰ Based on reduction in baseline HDRS scores at the end of the trial, 69% of patients achieved response and 46% met remission criteria; however, one-half of patients relapsed within 6 months.

Importantly, no cognitive adverse effects were observed. Furthermore, the antidepressant and anti-anxiety effects of MST were associated with localized metabolic changes in brain areas implicated in the pathophysiology of depression.

The investigators concluded that MST might constitute an effective, well-tolerated, and safe treatment for patients unable to benefit from available medical therapies for depression. In addition to confirmation of acute benefit in more definitive trials, the issue of durability of effect needs further clarification.

TMS is a key component of neuropsychiatric practice
It has been 3 decades since Barker et al³¹ developed the technology to deliver intense, localized magnetic pulses to specific areas of the nervous system. During this period, the role of TMS as a probe of the central and peripheral nervous systems has expanded to include various therapeutic applications, primarily focusing on treatment-resistant major depressive disorder.

Now, increasing sophistication in the choice of stimulation parameters and other ongoing efforts to optimize the benefits of TMS are yielding improved clinical outcomes. Research is still needed to better define the place of TMS in the management of subtypes of depression that are particularly difficult to treat and that do not benefit adequately from medications or psychotherapy or their combination.

Growing support from controlled trials, systematic reviews, meta-analyses, naturalistic outcome studies, and professional guidelines indicate that TMS has an increasingly important role in clinical practice.

Since 2008, the FDA has cleared 4 transcranial magnetic stimulation (TMS) devices for treating depression (Related Resources). In that time, the availability of TMS has steadily grown within and outside the United States.

Parallel with increasing clinical utilization of this technology, research continues into the benefit of TMS for treatment-resistant depression; such research includes additional, supportive, acute, sham-controlled trials; comparison trials with electroconvulsive therapy (ECT) for more severe episodes of depression; short- and long-term real-world outcome studies; exploration of alternative treatment parameters to further enhance its efficacy; and the development of other TMS approaches. In this article, we review recent developments in the application of TMS to treat major depressive disorder—in particular, treatment-resistant depression (Box).
 

Therapeutic neuromodulation
The underlying premise of neuromodulation is that the brain is an electrochemical organ that can be modulated by pharmacotherapy or device-based approaches, or their combination.¹ ECT is the prototypic device-based neuromodulation approach, and remains one of the most effective treatments for severe depression.

More recently, however, other methods have been, and continue to be, developed to treat patients who do not achieve adequate benefit from psychotherapy or medical therapy, or both, and who might not be an ideal candidate for ECT (Table,¹). In addition to the potential therapeutic benefit of these alternative strategies, some could avoid safety and tolerability concerns associated with medication (weight gain, sexual dysfunction) and ECT (eg, cognitive deficits).

TMS, which utilizes intense, localized magnetic fields to alter activity in neural circuits implicated in the pathophysiology of depression, represents an important example of this initiative.²

TMS has established efficacy for depression
Sham-controlled trials. Several randomized, sham-controlled acute trials have demonstrated the efficacy of TMS for treatment-resistant depression.

A recent meta-analysis considered 18 studies (N = 1,970) that met the authors’ criteria for inclusion.³ They found that TMS monotherapy was statistically and clinically more effective than a sham procedure based on:

• improvement in depressive symptoms (mean decrease in baseline Hamilton Depression Rating Scale [HDRS] score, −4.53 [95% CI, −6.11 to −2.96])
• response rate; response was 3 times more likely with TMS (relative risk 3.38 [95% CI, 2.24 to 5.10])
• remission rate; remission was 5 times more likely with TMS (relative risk, 5.07 [95% CI, 2.50 to 10.30]).

Another meta-analysis (7 studies, N = 279) considered TMS as an augmentation strategy to standard medication for treatment-resistant depression.⁴ The authors reported that, based on change in HDRS scores, the pooled standardized mean difference between active and sham TMS augmentation was 0.86 (P < .00001). Furthermore, the pooled response rate with TMS augmentation was 46.6%, compared with 22.1% with the sham procedure (P < .0003).

Acute naturalistic TMS studies. The efficacy of TMS is supported by a large, naturalistic study of 307 patients with treatment-resistant depression who were assessed at baseline and during a standard course of TMS.⁵ Considering change score in the Clinician Global Impressions-Severity (CGI-S) scale, significant improvement was seen from baseline to end of treatment (−1.9 ± 1.4; P < .0001), with a clinician-assessed response rate of 58.0% and remission rate of 37.1%. Of note: Self-reported quality-of-life measures (on the Medical Outcomes Study 36-Item Short-Form Health Survey and EuroQol 5-Dimensions) also significantly improved during this relatively brief period.⁶

Maintenance strategies after acute TMS response. Most patients referred for TMS have a depressive illness characterized by a chronic, relapsing course and inadequate response to pharmacotherapy or psychotherapy, or their combination. An effective maintenance strategy after acute response to TMS is paramount. This includes:

• prolonged tapering schedule after an acute TMS course is completed
• maintenance medication or psychotherapy, or both
• scheduled periodic maintenance TMS sessions (usually as an augmentation strategy)
• reintroduction of TMS as needed with early signs of relapse. In this context, several trials have assessed the durability of acute TMS benefit.

A semi-controlled maintenance study followed 99 patients who had at least a 25% decrease in baseline HDRS score after acute TMS treatment.⁷ They were then tapered from their TMS sessions over 3 weeks while an antidepressant was titrated up. If, at any time during the subsequent 6 months, early signs of depression relapse were noted (ie, change of at least 1 point on the CGI-S for 2 consecutive weeks), TMS was reintroduced. At the end of the trial, 10 patients (13%) had relapsed and 38 (38%) had an exacerbation of symptoms sufficient to warrant reintroduction of TMS. Of those, 32 (84%) re-achieved mood stability.

In another study, 50 patients who had achieved remission during an acute course of TMS were followed for 3 months.⁸ After TMS taper and continued pharmacotherapy or naturalistic follow-up, 29 (58%) remained in remission; 2 (4%) maintained partial response; and 1 (2%) relapsed.

In a controlled, pilot, maintenance trial, 67 unmedicated patients with treatment-resistant depression received an acute course of TMS.⁹ Forty-seven of the responders were then randomized to a 1-year follow-up trial with or without a scheduled monthly TMS session. All patients could receive reintroduction TMS if they met criteria for symptom worsening.

Both groups had a similar outcome. The number of patients who did not require TMS reintroduction was 9 of 23 (39%) in the scheduled TMS group vs 9 of 26 (35%) in the no-scheduled TMS group (P < .1). Although no difference was noted between groups, the authors commented that these preliminary results will help inform larger, more definitive trials. They concluded that both acute and maintenance TMS monotherapy might be an option—for some patients.

A long-term, naturalistic outcomes study followed 257 treatment-resistant depressed patients for 1 year after they responded to an acute course of TMS.¹⁰ In addition to most patients receiving ongoing maintenance medication, they also could receive reintroduction of TMS if symptoms became worse.

Compared with pre-TMS baseline, there was a statistically significant reduction in the mean total score on the CGI-S scale (primary outcome, P < .0001) at the end of acute treatment that was sustained at follow-up. Ninety-six patients (36.2%) required reintroduction of TMS and 75 of 120 (62.5%) who initially met response or remission criteria after acute treatment continued to meet response criteria after 1 year. The authors concluded that TMS demonstrated both a statistically and clinically meaningful durability of acute benefit during this time frame.

TMS and electroconvulsive therapy
For more than 75 years, ECT has consistently proved to be an effective treatment for major depressive disorder. Although the use of ECT has fluctuated over this period, one practice survey estimated that 100,000 patients receive ECT annually.¹¹

ECT has limitations, however, including cost, the need for general anesthesia, and cognitive deficits that range from short-term confusion to anterograde and retrograde amnesia, which can persist for weeks beyond active treatment.¹² Despite increasing awareness of mental illness, stigma also remains a significant barrier to receiving ECT.

TMS vs ECT. Several trials have directly compared ECT and TMS:

• A recent meta-analysis of 9 trials included 384 patients with depression who were considered clinically appropriate for ECT and were randomized to one or the other treatment.¹³ Both modalities produced a significant reduction in baseline HDRS score, but ECT (15.4 point reduction) was superior to TMS (9.3 point reduction) in the degree of improvement (P < .01).
• Another meta-analysis of 9 trials (N = 425) found ECT superior to TMS in terms of response (P < .03) and remission (P < .006) rates, based on improvement in the HDRS score.¹⁴ When psychotic depressed patients were excluded, however, TMS produced effects equivalent to ECT.

In contrast to what was seen with ECT, cognitive testing of patients who received TMS revealed no deterioration in any domain. Furthermore, one of the comparison studies observed a modest, but statistically significant, improvement in patient’s working memory-executive function, objective memory, and fine-motor speed over the course of TMS treatment.¹⁵

TMS plus ECT. A 2-week, randomized, single-blind, controlled pilot study (N = 22) examined the combination of TMS and ECT as acute treatment of depression.¹⁶ Patients were assigned to receive either unilateral non-dominant (UND) ECT 3 days a week or a combination of 1 UND ECT treatment followed by 4 days of TMS. At the conclusion of treatment, UND ECT plus TMS group produced comparable efficacy and fewer adverse effects compared with the UND ECT-only group.

TMS maintenance after acute ECT response. Most patients who are referred for ECT have a depressive illness characterized by repeated episodes and incomplete response to pharmacotherapy or psychotherapy, or both. The need for an effective maintenance strategy after the acute response is therefore critical. Medication or ECT, or both, are commonly used to maintain acute benefit but, regrettably, a recent systematic review of the durability of benefit with such strategies found a substantial percentage (approximately 50%) of patients relapsed within the first year.¹⁷

• In this context, a case series report found that 1 or 2 weekly, sequential, bilateral TMS treatments after a successful acute course of ECT maintained response in 5 of 6 patients over 6 to 12 months.¹⁸
• Another case series (N = 6) transitioned stable patients from maintenance ECT to maintenance TMS, primarily because of adverse effects with ECT.¹⁹ With a mean frequency of 1 TMS treatment every 3.5 weeks, all 6 patients remained stable for as long as 6 months. Subsequently, 2 patients relapsed—1 at 8 months and 1 at 9 months.

Advantages of maintenance TMS over maintenance ECT include lower cost, fewer adverse effects (particularly cognitive deficits), and the ability to remain independent during the period of the treatment sessions.

TMS as an assessment tool for ECT response. TMS can be used to study excitability in cortical circuits. In a study, EEG potentials evoked by TMS before and after a course of ECT in 8 severely depressed patients revealed an increase in frontal cortical excitability, compared with baseline.²⁰ Such findings support the ability of ECT to produce synaptic potentiation in humans. Furthermore, to the extent that depression presents with alterations in frontal cortical excitability, serial EEG-TMS measurements might be an effective tool to guide and monitor treatment progress with ECT, as well as other forms of therapeutic modulation.

Summing up: TMS and ECT. Although a definitive comparative study is needed, available evidence suggests that TMS might be an alternative treatment in a subgroup of patients who are referred for ECT. Factors that might warrant considering TMS over ECT include:

• patient preference
• fear of anesthesia
• concern about cognitive deficits
• stigma.

Although TMS might offer a workable alternative to ECT for acute and maintenance treatment of depression in selected patients, further refinement of the delivery of TMS is also needed to (1) enhance its efficacy and (2) identify clinical and biological markers to better define this select population.

Standard TMS treatment parameters
Superficial TMS. Superficial TMS for depression typically involves a single coil placed over the left dorsolateral prefrontal cortex. The standard, FDA-approved protocol includes stimulating at 110% of motor threshold with 75, 4-second trains at 10 Hz (ie, 40 stimulations) interspersed by 26-second intertrain intervals. Without interruption, a standard treatment session takes 37.5 minutes and delivers a total of 3,000 pulses. Most patients require 20 to 30 sessions, on a Monday-through-Friday schedule, to achieve optimal benefit.

This approach stimulates to a depth of approximately 2 or 3 cm. The coil usually is placed over the left dorsolateral prefrontal cortex because earlier studies indicated that decreased activity in this part of the brain correlates with symptoms of depression. When TMS is administered in a rapid repetitive fashion (at >1 Hz; typically, at 10 Hz), blood flow and metabolism in that area of the brain are increased. In addition, imaging studies indicate that trans-synaptic connections with deeper parts of the brain also allow modulation of other relevant neural circuits.

An alternate approach, less well-studied, involves low-frequency stimulation over the right dorsolateral prefrontal cortex. Parameters differ from what is used in left high-frequency dorsolateral prefrontal cortex TMS: frequency <1 Hz; train durations as long as 15 minutes; an intertrain interval of 25 to 180 seconds; 120 to 900 stimulations per train; and 2,400 to 18,000 total stimulations.

One hypothesis is that this low-frequency approach selectively stimulates inhibitory interneurons, decreases local neuronal activity and diminishes blood flow to deeper structures, such as the amygdala. Although right low-frequency TMS, compared with left high-frequency TMS, has potential advantages of better tolerability and decreased risk for seizures, its relative efficacy is unclear.

Deep TMS. Studies also are pursuing different coil configurations that allow for more direct stimulation of relevant structures (eg, prefrontal neuronal pathways associated with the reward system).

One of these coil designs (ie, the H-coil), coupled to a Magstim TMS stimulator, recently received FDA clearance for treatment-resistant depression. In the pivotal, sham-controlled study, patients received 20 treatment sessions over 4 weeks.²¹ The treatment protocol consisted of a helmet-like coil placed over the medial and lateral prefrontal cortex. Stimulation parameters included an 18-Hz frequency; stimulation intensity of 120% motor threshold; stimulation train duration of 2 seconds; and an intertrain interval of 20 seconds. The treatment sessions lasted 20.2 minutes and delivered a total of 1,980 stimulations.

Based on the 21-item HDRS, the active treatment coil group achieved a significantly greater decrease in baseline score (6.39 vs 3.28; P < .008); a greater response rate (37% vs 27.8%; P < .03); and a greater remission rate (30.4% vs 15.8%; P < .016) compared with the sham coil group.

Next, in what is the only randomized, controlled maintenance assessment to date, the same patients were followed for an additional 12 weeks, continuing blinded treatments twice weekly. At the end of the second phase, the active treatment group also demonstrated greater benefit than the sham group (P < .03). One seizure did occur, possibly related to excessive alcohol use; but this raises the question of whether treating at a higher frequency (18 Hz) with greater depth and less focality might increase the risk of seizure.

To assess the potential advantages, as well as the relative safety, of this approach over standard TMS delivery, an adequately designed and powered trial comparing the H-coil and a single-coil device is needed.

Alternate TMS approaches
Efforts to improve the clinical effectiveness of TMS for treating depression include several approaches.

Theta burst stimulation (TBS) is a patterned form of TMS pulse delivery that utilizes high and low frequencies in the same stimulus train (eg, three 50-Hz bursts delivered 5 times a second). Such a pulse sequence can modulate long-term depression and long-term potentiation mechanisms that induce plasticity in areas such as the hippocampus.²²

Intermittent TBS (iTBS) administers stimulations over a relatively brief duration (eg, 2 seconds) or intermittently (eg, every 10 seconds) for a specific period (eg, 190 seconds [600 pulses in total]) over the left dorsolateral prefrontal cortex. This technique induces long-term potentiation and produces effects similar to those of high-frequency TMS.

In contrast, continuous TBS (cTBS) administers a continuous train (eg, 40 seconds [600 total pulses]) over the right dorsolateral prefrontal cortex. This induces long-term depression and produces effects similar to low-frequency TMS.

Recent studies using different delivery paradigms have generated mixed results:

Study 1: Fifty-six patients with depression received active treatment; 17 others, a sham procedure.²³ This study used 3 different conditions:

• a combination of low-frequency and high-frequency TMS stimulation, administered over the right and left dorsolateral prefrontal cortices, respectively
• a combination of iTBS over the left dorsolateral prefrontal cortex and cTBS over the right dorsolateral prefrontal cortex
• a sham procedure, in which no magnetic field was created.

Neither active treatment arm separated from the sham procedure based on change scores in the 21-item HDRS (P = not significant).

Study 2: Sixty treatment-resistant depression patients were assigned to cTBS, iTBS, a combination of the 2 procedures, or a sham procedure.²⁴ After 2 weeks, the active treatment arms produced the greatest benefit, based on change in scores on the 17-item HDRS, which differed significantly among the 4 groups (F value = 6.166; P < .001); the iTBS and combination arms demonstrated the most robust effect.

There were also significantly more responders in the iTBS (40.0%) and combination groups (66.7%) than in the cTBS (25.0%) and sham groups (13.3%) (P < .010). A lower level of treatment refractoriness predicted a better outcome.

Study 3: Twenty-nine depressed patients were randomized to cTBS over the right dorsolateral prefrontal cortex or a sham procedure.²⁵ Overall, there was no difference between groups; however, actively treated patients who were unmedicated (n = 3) or remained on a stable dosage of medication during treatment (n = 8) did experience a significantly greater reduction in the HDRS score.

Study 4: In a pilot trial, 32 depressed patients were randomized to 30 sessions of adjunctive combined iTBS plus cTBS or bilateral sham TBS.²⁶ Based on reduction from the baseline Montgomery-Åsberg Depression Rating Scale score, 9 patients in the active treatment group and 4 in the sham group achieved response (odds ratio, 3.86; P < .048).

If at least comparable efficacy can be clearly demonstrated, advantages of TBS over standard TMS include a significantly reduced administration time, which might allow for more patients to be treated and reduce associated costs of treatment.²⁷

Magnetic low-field synchronized stimulation is produced by rotating spherical rare-earth magnets that are synchronized to an individual’s alpha frequency. A recent 6-week, double-blind, sham-controlled trial (N = 202) reported that, in the intention-to-treat population, there was no difference in outcome between treatment arms. In patients who completed the study according to protocol (120 of 202), however, active treatment was significantly better in decreasing baseline HDRS score (P < .033).²⁸

Magnetic seizure therapy (MST) is an experimental approach to treating patients with more severe depression that is resistant to medical therapy. The primary aim is to use TMS to induce a seizure, thus achieving the same efficacy as provided by ECT but without the adverse cognitive effects of ECT. With MST, the TMS device uses much higher stimulation settings to produce a seizure—the goal being to avoid direct electrical current to the brain’s memory centers.²⁹

A pilot study considered the clinical and cognitive effects of MST in a group of 26 treatment-resistant depression patients (10 randomized; 16 open-label).³⁰ Based on reduction in baseline HDRS scores at the end of the trial, 69% of patients achieved response and 46% met remission criteria; however, one-half of patients relapsed within 6 months.

Importantly, no cognitive adverse effects were observed. Furthermore, the antidepressant and anti-anxiety effects of MST were associated with localized metabolic changes in brain areas implicated in the pathophysiology of depression.

The investigators concluded that MST might constitute an effective, well-tolerated, and safe treatment for patients unable to benefit from available medical therapies for depression. In addition to confirmation of acute benefit in more definitive trials, the issue of durability of effect needs further clarification.

TMS is a key component of neuropsychiatric practice
It has been 3 decades since Barker et al³¹ developed the technology to deliver intense, localized magnetic pulses to specific areas of the nervous system. During this period, the role of TMS as a probe of the central and peripheral nervous systems has expanded to include various therapeutic applications, primarily focusing on treatment-resistant major depressive disorder.

Now, increasing sophistication in the choice of stimulation parameters and other ongoing efforts to optimize the benefits of TMS are yielding improved clinical outcomes. Research is still needed to better define the place of TMS in the management of subtypes of depression that are particularly difficult to treat and that do not benefit adequately from medications or psychotherapy or their combination.

Growing support from controlled trials, systematic reviews, meta-analyses, naturalistic outcome studies, and professional guidelines indicate that TMS has an increasingly important role in clinical practice.