Current Psychiatry

CASE: He bares it all

Police have arrested Mr. L, age 62, 3 times in 36 hours after spotting him walking naked in public. With the county jail jammed to capacity, police bring him each time to our hospital’s emergency room.

After his first arrest, Mr. L matter-of-factly tells us, “I want to walk naked and starve myself to death.” His self-harm exhortations amplify with each visit until—at the third presentation—he reports that he has not eaten for at least 2 days.

Mr. L had been living on the streets for nearly 1 month. Before that, he had been in jail for approximately 1 month after attacking a nursing home patient. He has been hospitalized twice in 5 months for severe depression and personality disorder and has engaged in numerous disruptive behavioral episodes and feeble suicide attempts. At this latest presentation, he appears disheveled and lacks judgment and insight into his condition.

We readmit Mr. L to the psychiatric unit to re-evaluate his treatment. He had been on citalopram, 60 mg/d, and aripiprazole, 10 mg/d, but he says he stopped taking the medications because they were not improving his mood.

The authors’ observations

We readmitted Mr. L with working diagnoses of:

• major depressive disorder with psychotic features, based on his suicide threats and complaints of depression
  
• personality disorder not otherwise specified, based on his behavioral episodes, apparent desire to be cared for (Table 1), and refusal to “get better” during 2 recent hospitalizations.
  

Table 1

A troubled life: Mr. L’s history

Period	Mr. L’s difficulties
Childhood	Has no friends in school; his mother—Mr. L’s sole source of emotional support—continues to wash his laundry, buy his food and clothes into his 20s
Adult life	Keeps ‘goofing off’ at work and has trouble staying employed; depends on wife to manage his life
2 years ago	Shows depressive symptoms (amotivation, lack of concentration, increased fatigue, decreased appetite) after shoulder injury Develops irrational fear that household appliances will malfunction Becomes hostile toward his wife of 34 years
5 months ago	Hospitalized after threatening to kill wife; has depressive symptoms and is disruptive during month-long hospitalization
4 months ago	Discharged from hospital to homeless shelter because estranged wife won’t allow him back home; is readmitted after shelter staff find him banging his head on an iron gate; again behaves disruptively
3 months ago	Discharged from second month-long hospitalization to nursing home
2 months ago	Attacks patient at nursing home; police arrest and incarcerate him on disorderly conduct charge
Past month	Released from jail after 1 month and spends weeks on the streets; lands in ER after police repeatedly catch him walking naked in public

HISTORY: His best friends

As a child, Mr. L had no friends. His father was physically present but emotionally distant, so he relied on his mother for emotional support. Throughout his teens and early adulthood, his mother continued to do his laundry, buy his food and clothes, and run his life. When he married in his early 20s, his wife assumed this role.

Mr. L avoided psychiatric care for most of his life but did not socialize outside the house, lacked ambition, and seemed content to depend on his wife. He worked primarily as a janitor or housekeeper but was constantly getting fired and drifted from job to job. His wife told us that when he was supposed to be working, he spent hours staring at the walls and watching TV.

Mr. L’s recent troubles began approximately 2 years ago, when he suffered a shoulder injury. He underwent physical therapy but refused needed surgery because he lacked money and health insurance.

As the shoulder pain intensified, Mr. L quit his job. While out of work, he stopped attending physical therapy sessions when his depressive symptoms began to offset the shoulder pain. He suffered loss of concentration and motivation, increased fatigue with hypersomnia, and decreased appetite. He lost 10 to 12 lb in 1 year.

Mr. L also started having trouble “focusing on reality” and developed obsessive fears of malfunctions around the house, such as the furnace blowing up, the stove catching fire, or the toilet backing up. At one point, he began urinating and defecating in his pants to avoid using the toilet. He began to feel hopeless and several times tried to suffocate himself by placing a plastic bag over his head.

He also grew irritable, angry, and aggressive—mostly toward his wife, who increasingly feared him. He started blaming her for “everything wrong in my life” and began contemplating stabbing her to death or striking her head with a hammer.

 

Five months ago, Mr. L was involuntarily hospitalized for depressive symptoms, suicidality, and continued homicidal thoughts toward his wife. The attending psychiatrist started olanzapine, 5 mg nightly, for psychotic features, and citalopram, 10 mg/d, for depression and anxiety, and ordered one-on-one observation to prevent additional suicide attempts. Mr. L’s shoulder pain had resolved by this time.

Three days later, Mr. L began refusing to eat. The psychiatrist then increased citalopram to 20 mg/d and olanzapine to 5 mg bid and asked a hospital internist to evaluate for malnutrition and a psychologist to gauge cognitive and intellectual function.

During the psychologist’s evaluation, Mr. L showed average global intellectual functioning but delays in visual-motor speed, visual working memory, and alertness to his environment. These findings, however, did not explain the patient’s lower functioning at home or in the hospital.

We ruled out organic causes for Mr. L’s cognitive deficits after receiving normal brain MRI, urinalysis, rapid plasma reagin titer, and thyroid-stimulating hormone test results. We also ruled out malnutrition because vitamin B12 and folate levels were normal but ordered a dietary consult to help Mr. L regain weight.

Staff and family registered Mr. L for Medicare and Medicaid benefits so that he could become more independent, but his behavior soon regressed. He complained that staff and family were ignoring him and started urinating outside the bathroom, eating and smearing his feces, and bothering other patients. Staff directed Mr. L’s wife to ignore his verbal abuse over the phone and encourage him to stay motivated for treatment.

Mr. L’s disruptive behavior stopped after the psychologist tried individual therapy with behavior modification. The psychologist helped him devise a cleanliness plan and encouraged him to express his anger verbally rather than acting out. When Mr. L smeared his feces, he was to scrub the area with soap and water, take a 5-minute cold shower, put on clean clothes, and write and read an apology to hospital staff.

DISCHARGE: Nowhere to go

One month after admission, Mr. L was free of suicidal and homicidal thoughts and other symptoms. Staff prepared him for discharge, but his wife was contemplating divorce and refused to allow him back home. He also declined community outpatient treatment because he wanted his life to return to “normal” and was unaware that he was harming himself and others.

With no other disposition options, we discharged Mr. L to a homeless shelter. Later that day, shelter staff brought him back to the ER after they found him banging his head against an iron gate. We readmitted him to the psychiatric unit, at which point he endorsed suicidal thinking.

READMISSION: ‘Cold’ case

During this second hospitalization, Mr. L was again eating his feces as well as coloring himself with green markers, writing obscenities on the wall, and tearing up other patients’ papers. He repeatedly took 15-minute cold showers and told staff as they urged him out of the shower that he wanted to die by inducing hypothermia. During these episodes, he often called his estranged wife and told her what he was doing.

After the treatment team had Mr. L civilly committed, the attending psychiatrist titrated citalopram to 60 mg/d, discontinued olanzapine, and added aripiprazole to target the patient’s underlying depressive symptoms. Aripiprazole was started at 5 mg nightly and eventually titrated to 10 mg nightly. On 3 occasions during the month-long hospitalization, Mr. L refused to take his medications because he felt he did not belong in the hospital.

The attending psychiatrist diagnosed “dependent, passive-aggressive behaviors” and noted that Mr. L was “not amenable” to psychiatric hospitalization. The treatment team and outpatient community mental health department decided the patient had a personality disorder and that continued hospitalization would prevent him from attaining autonomy.

We then discharged Mr. L to a nursing home. There, he demanded a transfer back to the hospital or to jail because he feared he could not afford nursing home care and believed he could receive more attention elsewhere. His request was rejected after our ER psychiatrist found him medically and mentally fit to stay at the nursing home.

About 1 month later, Mr. L tried to smother a female patient by holding a pillow over her face but stopped when she began to struggle. After he told the nurses what he had done, staff immediately called police, who arrested Mr. L and transferred him to the county jail.

Because police and nursing home staff viewed the incident as a cry for help rather than a cold-blooded attack, police charged Mr. L with disorderly conduct. One month later, police dropped the charge and released him to the streets.

 

The authors’ observations

Mr. L triggered hateful reactions among several treatment team members, many of whom felt vindicated by his arrest. Clinicians might react this way if they feel a patient is wasting their time, manipulating them, not recognizing their narcissistic need for the patient to change, or ignoring their treatment plans.¹

Acknowledging the staff’s—and your own—reaction to a difficult patient is critical. Not doing so can lead to treatment decisions based on emotions rather than evidence. In a busy clinical setting, it’s easy to lose sight of this.

The following strategies can help you manage hateful countertransference, cope with a patient’s offensive behaviors, and make appropriate decisions:

• Allow staff members to discuss their feelings. Encourage them to acknowledge and discuss their feelings during team meetings or daily treatment discussions. This helped members of our team recognize that their identification with Mr. L’s self-rejection fueled their desire to “reject” him by discharging him to police or the homeless shelter.
  
• Joke about the patient’s behavior when appropriate. Humor is a mature and potentially healing defense mechanism. When not treating Mr. L, for example, we joked among ourselves about publishing a case report titled, “The case of the poop-eater.” Never joke about the patient in the therapeutic milieu, where it can be disruptive.
  
• See the behavior as a defense mechanism. Viewing patients’ reactions as defense mechanisms—rather than effects of a psychiatric disorder—can help you better understand the patient’s underlying pathophysiology.
  

READMISSION: More bad behavior

After his 3 arrests for public nudity, we readmit Mr. L, restart citalopram at 20 mg/d, and titrate it back to 60 mg/d to target his depression. We also switch back to olanzapine, 10 mg nightly, because the patient has seen little clinical benefit from aripiprazole and feels that olanzapine had improved his sleep.

In the psychiatric ward, Mr. L is once again disturbing patients, smearing and eating feces, and making half-hearted suicide attempts. Upset that staff is “ignoring” him, he enters other patients’ rooms without invitation and urinates in places other than the bathroom.

The authors’ observations

After 3 hospital admissions, Mr. L’s diagnosis remained unclear (Table 2). At his first admission, his symptoms suggested major depression with psychotic features. With his subsequent behaviors in the inpatient psychiatric unit—including primitive suicide attempts and smearing and eating feces—Mr. L showed a strong desire to be cared for. This and his past dependence on his wife and mother suggested a severe dependent personality disorder.

At his first discharge, Mr. L was diagnosed with a personality disorder with significant passive-aggressive traits. His lifelong dysphoria and lack of ambition also suggested dysthymia.

With discharge from this latest hospitalization pending, we searched for options. We considered Mr. L’s ongoing suicidality, persistent acting out, and aggression. Treatment team members discussed his use of “primitive defenses”² stemming from his limited coping skills in the face of severe depression.

Table 2

Mr. L’s differential diagnosis

Possible diagnosis	Mr. L’s symptoms
Major depression	Diminished motivation, concentration, and appetite Increased fatigue, hypersomnia Suicidal thinking
Personality disorder	Primitive, dependent behaviors Abnormal dependence on wife, mother
Depression with psychotic features	Depressive symptoms with obsessive suicidal/homicidal thoughts, fears of household malfunctions

TREATMENT: A different course

One week after admission, Mr. L’s inpatient psychiatrist recommends electroconvulsive therapy (ECT) to target the patient’s presumed severe depressive episodes and disruptive behaviors. The psychiatrist is experienced in performing ECT, which in clinical trials³ has shown efficacy in treatment-refractory major depression.

After giving informed consent, Mr. L receives 8 bilateral ECT treatments in 3 weeks. Also, the hospital psychologist performs behavioral modification similar to the previous cleanliness plan and again encourages Mr. L to express his anger and anxiety verbally.

By the second week of ECT, Mr. L’s disruptive behaviors have ceased. By the end of week 3, his mood and motivation have improved to the point where he shows interest in becoming independent. He says he wants to show his estranged wife he can care for himself and eventually reunite with her.

As Mr. L continues to improve, we discharge him to outpatient community mental health services and continue citalopram, 60 mg/d, and olanzapine, 5 mg nightly.

Nearly 2 years later, Mr. L is living independently. He has been regularly seeing his psychiatrist at the community mental health center and is maintained on citalopram and olanzapine. He continues trying to make amends with his wife but is still out of work and receives Social Security disability benefits.

The authors’ observations

Mr. L was fortunate that his inpatient psychiatrist could re-evaluate the diagnosis after identifying the staff’s significantly hateful countertransference. This allowed staff to offer ECT, which—despite its documented efficacy for major depression—is not widely available in the United States.

 

If no ECT providers were available, we would have considered medication change and long-term treatment in a state mental hospital until Mr. L showed he could care for himself.

Related resources

• Nagera H. Countertransference (PowerPoint presentation). Tampa, FL: The Carter Jenkins Center; 2003. www.thecjc.org/ppoint/ppoint/ct.ppt.
  
• MayoClinic.com video: Electroconvulsive therapy (ECT): One woman’s journey. Click on “Video” at top, then scroll to title.
  

Drug brand names

• Aripiprazole • Abilify
  
• Olanzapine • Zyprexa
  
• Citalopram • Celexa
  

Disclosure

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

CASE: He bares it all

Police have arrested Mr. L, age 62, 3 times in 36 hours after spotting him walking naked in public. With the county jail jammed to capacity, police bring him each time to our hospital’s emergency room.

After his first arrest, Mr. L matter-of-factly tells us, “I want to walk naked and starve myself to death.” His self-harm exhortations amplify with each visit until—at the third presentation—he reports that he has not eaten for at least 2 days.

Mr. L had been living on the streets for nearly 1 month. Before that, he had been in jail for approximately 1 month after attacking a nursing home patient. He has been hospitalized twice in 5 months for severe depression and personality disorder and has engaged in numerous disruptive behavioral episodes and feeble suicide attempts. At this latest presentation, he appears disheveled and lacks judgment and insight into his condition.

We readmit Mr. L to the psychiatric unit to re-evaluate his treatment. He had been on citalopram, 60 mg/d, and aripiprazole, 10 mg/d, but he says he stopped taking the medications because they were not improving his mood.

The authors’ observations

We readmitted Mr. L with working diagnoses of:

• major depressive disorder with psychotic features, based on his suicide threats and complaints of depression
  
• personality disorder not otherwise specified, based on his behavioral episodes, apparent desire to be cared for (Table 1), and refusal to “get better” during 2 recent hospitalizations.
  

Table 1

A troubled life: Mr. L’s history

Period	Mr. L’s difficulties
Childhood	Has no friends in school; his mother—Mr. L’s sole source of emotional support—continues to wash his laundry, buy his food and clothes into his 20s
Adult life	Keeps ‘goofing off’ at work and has trouble staying employed; depends on wife to manage his life
2 years ago	Shows depressive symptoms (amotivation, lack of concentration, increased fatigue, decreased appetite) after shoulder injury Develops irrational fear that household appliances will malfunction Becomes hostile toward his wife of 34 years
5 months ago	Hospitalized after threatening to kill wife; has depressive symptoms and is disruptive during month-long hospitalization
4 months ago	Discharged from hospital to homeless shelter because estranged wife won’t allow him back home; is readmitted after shelter staff find him banging his head on an iron gate; again behaves disruptively
3 months ago	Discharged from second month-long hospitalization to nursing home
2 months ago	Attacks patient at nursing home; police arrest and incarcerate him on disorderly conduct charge
Past month	Released from jail after 1 month and spends weeks on the streets; lands in ER after police repeatedly catch him walking naked in public

HISTORY: His best friends

As a child, Mr. L had no friends. His father was physically present but emotionally distant, so he relied on his mother for emotional support. Throughout his teens and early adulthood, his mother continued to do his laundry, buy his food and clothes, and run his life. When he married in his early 20s, his wife assumed this role.

Mr. L avoided psychiatric care for most of his life but did not socialize outside the house, lacked ambition, and seemed content to depend on his wife. He worked primarily as a janitor or housekeeper but was constantly getting fired and drifted from job to job. His wife told us that when he was supposed to be working, he spent hours staring at the walls and watching TV.

Mr. L’s recent troubles began approximately 2 years ago, when he suffered a shoulder injury. He underwent physical therapy but refused needed surgery because he lacked money and health insurance.

As the shoulder pain intensified, Mr. L quit his job. While out of work, he stopped attending physical therapy sessions when his depressive symptoms began to offset the shoulder pain. He suffered loss of concentration and motivation, increased fatigue with hypersomnia, and decreased appetite. He lost 10 to 12 lb in 1 year.

Mr. L also started having trouble “focusing on reality” and developed obsessive fears of malfunctions around the house, such as the furnace blowing up, the stove catching fire, or the toilet backing up. At one point, he began urinating and defecating in his pants to avoid using the toilet. He began to feel hopeless and several times tried to suffocate himself by placing a plastic bag over his head.

He also grew irritable, angry, and aggressive—mostly toward his wife, who increasingly feared him. He started blaming her for “everything wrong in my life” and began contemplating stabbing her to death or striking her head with a hammer.

 

Five months ago, Mr. L was involuntarily hospitalized for depressive symptoms, suicidality, and continued homicidal thoughts toward his wife. The attending psychiatrist started olanzapine, 5 mg nightly, for psychotic features, and citalopram, 10 mg/d, for depression and anxiety, and ordered one-on-one observation to prevent additional suicide attempts. Mr. L’s shoulder pain had resolved by this time.

Three days later, Mr. L began refusing to eat. The psychiatrist then increased citalopram to 20 mg/d and olanzapine to 5 mg bid and asked a hospital internist to evaluate for malnutrition and a psychologist to gauge cognitive and intellectual function.

During the psychologist’s evaluation, Mr. L showed average global intellectual functioning but delays in visual-motor speed, visual working memory, and alertness to his environment. These findings, however, did not explain the patient’s lower functioning at home or in the hospital.

We ruled out organic causes for Mr. L’s cognitive deficits after receiving normal brain MRI, urinalysis, rapid plasma reagin titer, and thyroid-stimulating hormone test results. We also ruled out malnutrition because vitamin B12 and folate levels were normal but ordered a dietary consult to help Mr. L regain weight.

Staff and family registered Mr. L for Medicare and Medicaid benefits so that he could become more independent, but his behavior soon regressed. He complained that staff and family were ignoring him and started urinating outside the bathroom, eating and smearing his feces, and bothering other patients. Staff directed Mr. L’s wife to ignore his verbal abuse over the phone and encourage him to stay motivated for treatment.

Mr. L’s disruptive behavior stopped after the psychologist tried individual therapy with behavior modification. The psychologist helped him devise a cleanliness plan and encouraged him to express his anger verbally rather than acting out. When Mr. L smeared his feces, he was to scrub the area with soap and water, take a 5-minute cold shower, put on clean clothes, and write and read an apology to hospital staff.

DISCHARGE: Nowhere to go

One month after admission, Mr. L was free of suicidal and homicidal thoughts and other symptoms. Staff prepared him for discharge, but his wife was contemplating divorce and refused to allow him back home. He also declined community outpatient treatment because he wanted his life to return to “normal” and was unaware that he was harming himself and others.

With no other disposition options, we discharged Mr. L to a homeless shelter. Later that day, shelter staff brought him back to the ER after they found him banging his head against an iron gate. We readmitted him to the psychiatric unit, at which point he endorsed suicidal thinking.

READMISSION: ‘Cold’ case

During this second hospitalization, Mr. L was again eating his feces as well as coloring himself with green markers, writing obscenities on the wall, and tearing up other patients’ papers. He repeatedly took 15-minute cold showers and told staff as they urged him out of the shower that he wanted to die by inducing hypothermia. During these episodes, he often called his estranged wife and told her what he was doing.

After the treatment team had Mr. L civilly committed, the attending psychiatrist titrated citalopram to 60 mg/d, discontinued olanzapine, and added aripiprazole to target the patient’s underlying depressive symptoms. Aripiprazole was started at 5 mg nightly and eventually titrated to 10 mg nightly. On 3 occasions during the month-long hospitalization, Mr. L refused to take his medications because he felt he did not belong in the hospital.

The attending psychiatrist diagnosed “dependent, passive-aggressive behaviors” and noted that Mr. L was “not amenable” to psychiatric hospitalization. The treatment team and outpatient community mental health department decided the patient had a personality disorder and that continued hospitalization would prevent him from attaining autonomy.

We then discharged Mr. L to a nursing home. There, he demanded a transfer back to the hospital or to jail because he feared he could not afford nursing home care and believed he could receive more attention elsewhere. His request was rejected after our ER psychiatrist found him medically and mentally fit to stay at the nursing home.

About 1 month later, Mr. L tried to smother a female patient by holding a pillow over her face but stopped when she began to struggle. After he told the nurses what he had done, staff immediately called police, who arrested Mr. L and transferred him to the county jail.

Because police and nursing home staff viewed the incident as a cry for help rather than a cold-blooded attack, police charged Mr. L with disorderly conduct. One month later, police dropped the charge and released him to the streets.

 

The authors’ observations

Mr. L triggered hateful reactions among several treatment team members, many of whom felt vindicated by his arrest. Clinicians might react this way if they feel a patient is wasting their time, manipulating them, not recognizing their narcissistic need for the patient to change, or ignoring their treatment plans.¹

Acknowledging the staff’s—and your own—reaction to a difficult patient is critical. Not doing so can lead to treatment decisions based on emotions rather than evidence. In a busy clinical setting, it’s easy to lose sight of this.

The following strategies can help you manage hateful countertransference, cope with a patient’s offensive behaviors, and make appropriate decisions:

• Allow staff members to discuss their feelings. Encourage them to acknowledge and discuss their feelings during team meetings or daily treatment discussions. This helped members of our team recognize that their identification with Mr. L’s self-rejection fueled their desire to “reject” him by discharging him to police or the homeless shelter.
  
• Joke about the patient’s behavior when appropriate. Humor is a mature and potentially healing defense mechanism. When not treating Mr. L, for example, we joked among ourselves about publishing a case report titled, “The case of the poop-eater.” Never joke about the patient in the therapeutic milieu, where it can be disruptive.
  
• See the behavior as a defense mechanism. Viewing patients’ reactions as defense mechanisms—rather than effects of a psychiatric disorder—can help you better understand the patient’s underlying pathophysiology.
  

READMISSION: More bad behavior

After his 3 arrests for public nudity, we readmit Mr. L, restart citalopram at 20 mg/d, and titrate it back to 60 mg/d to target his depression. We also switch back to olanzapine, 10 mg nightly, because the patient has seen little clinical benefit from aripiprazole and feels that olanzapine had improved his sleep.

In the psychiatric ward, Mr. L is once again disturbing patients, smearing and eating feces, and making half-hearted suicide attempts. Upset that staff is “ignoring” him, he enters other patients’ rooms without invitation and urinates in places other than the bathroom.

The authors’ observations

After 3 hospital admissions, Mr. L’s diagnosis remained unclear (Table 2). At his first admission, his symptoms suggested major depression with psychotic features. With his subsequent behaviors in the inpatient psychiatric unit—including primitive suicide attempts and smearing and eating feces—Mr. L showed a strong desire to be cared for. This and his past dependence on his wife and mother suggested a severe dependent personality disorder.

At his first discharge, Mr. L was diagnosed with a personality disorder with significant passive-aggressive traits. His lifelong dysphoria and lack of ambition also suggested dysthymia.

With discharge from this latest hospitalization pending, we searched for options. We considered Mr. L’s ongoing suicidality, persistent acting out, and aggression. Treatment team members discussed his use of “primitive defenses”² stemming from his limited coping skills in the face of severe depression.

Table 2

Mr. L’s differential diagnosis

Possible diagnosis	Mr. L’s symptoms
Major depression	Diminished motivation, concentration, and appetite Increased fatigue, hypersomnia Suicidal thinking
Personality disorder	Primitive, dependent behaviors Abnormal dependence on wife, mother
Depression with psychotic features	Depressive symptoms with obsessive suicidal/homicidal thoughts, fears of household malfunctions

TREATMENT: A different course

One week after admission, Mr. L’s inpatient psychiatrist recommends electroconvulsive therapy (ECT) to target the patient’s presumed severe depressive episodes and disruptive behaviors. The psychiatrist is experienced in performing ECT, which in clinical trials³ has shown efficacy in treatment-refractory major depression.

After giving informed consent, Mr. L receives 8 bilateral ECT treatments in 3 weeks. Also, the hospital psychologist performs behavioral modification similar to the previous cleanliness plan and again encourages Mr. L to express his anger and anxiety verbally.

By the second week of ECT, Mr. L’s disruptive behaviors have ceased. By the end of week 3, his mood and motivation have improved to the point where he shows interest in becoming independent. He says he wants to show his estranged wife he can care for himself and eventually reunite with her.

As Mr. L continues to improve, we discharge him to outpatient community mental health services and continue citalopram, 60 mg/d, and olanzapine, 5 mg nightly.

Nearly 2 years later, Mr. L is living independently. He has been regularly seeing his psychiatrist at the community mental health center and is maintained on citalopram and olanzapine. He continues trying to make amends with his wife but is still out of work and receives Social Security disability benefits.

The authors’ observations

Mr. L was fortunate that his inpatient psychiatrist could re-evaluate the diagnosis after identifying the staff’s significantly hateful countertransference. This allowed staff to offer ECT, which—despite its documented efficacy for major depression—is not widely available in the United States.

 

If no ECT providers were available, we would have considered medication change and long-term treatment in a state mental hospital until Mr. L showed he could care for himself.

Related resources

• Nagera H. Countertransference (PowerPoint presentation). Tampa, FL: The Carter Jenkins Center; 2003. www.thecjc.org/ppoint/ppoint/ct.ppt.
  
• MayoClinic.com video: Electroconvulsive therapy (ECT): One woman’s journey. Click on “Video” at top, then scroll to title.
  

Drug brand names

• Aripiprazole • Abilify
  
• Olanzapine • Zyprexa
  
• Citalopram • Celexa
  

Disclosure

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

CASE: He bares it all

Police have arrested Mr. L, age 62, 3 times in 36 hours after spotting him walking naked in public. With the county jail jammed to capacity, police bring him each time to our hospital’s emergency room.

After his first arrest, Mr. L matter-of-factly tells us, “I want to walk naked and starve myself to death.” His self-harm exhortations amplify with each visit until—at the third presentation—he reports that he has not eaten for at least 2 days.

Mr. L had been living on the streets for nearly 1 month. Before that, he had been in jail for approximately 1 month after attacking a nursing home patient. He has been hospitalized twice in 5 months for severe depression and personality disorder and has engaged in numerous disruptive behavioral episodes and feeble suicide attempts. At this latest presentation, he appears disheveled and lacks judgment and insight into his condition.

We readmit Mr. L to the psychiatric unit to re-evaluate his treatment. He had been on citalopram, 60 mg/d, and aripiprazole, 10 mg/d, but he says he stopped taking the medications because they were not improving his mood.

The authors’ observations

We readmitted Mr. L with working diagnoses of:

• major depressive disorder with psychotic features, based on his suicide threats and complaints of depression
  
• personality disorder not otherwise specified, based on his behavioral episodes, apparent desire to be cared for (Table 1), and refusal to “get better” during 2 recent hospitalizations.
  

Table 1

A troubled life: Mr. L’s history

Period	Mr. L’s difficulties
Childhood	Has no friends in school; his mother—Mr. L’s sole source of emotional support—continues to wash his laundry, buy his food and clothes into his 20s
Adult life	Keeps ‘goofing off’ at work and has trouble staying employed; depends on wife to manage his life
2 years ago	Shows depressive symptoms (amotivation, lack of concentration, increased fatigue, decreased appetite) after shoulder injury Develops irrational fear that household appliances will malfunction Becomes hostile toward his wife of 34 years
5 months ago	Hospitalized after threatening to kill wife; has depressive symptoms and is disruptive during month-long hospitalization
4 months ago	Discharged from hospital to homeless shelter because estranged wife won’t allow him back home; is readmitted after shelter staff find him banging his head on an iron gate; again behaves disruptively
3 months ago	Discharged from second month-long hospitalization to nursing home
2 months ago	Attacks patient at nursing home; police arrest and incarcerate him on disorderly conduct charge
Past month	Released from jail after 1 month and spends weeks on the streets; lands in ER after police repeatedly catch him walking naked in public

HISTORY: His best friends

As a child, Mr. L had no friends. His father was physically present but emotionally distant, so he relied on his mother for emotional support. Throughout his teens and early adulthood, his mother continued to do his laundry, buy his food and clothes, and run his life. When he married in his early 20s, his wife assumed this role.

Mr. L avoided psychiatric care for most of his life but did not socialize outside the house, lacked ambition, and seemed content to depend on his wife. He worked primarily as a janitor or housekeeper but was constantly getting fired and drifted from job to job. His wife told us that when he was supposed to be working, he spent hours staring at the walls and watching TV.

Mr. L’s recent troubles began approximately 2 years ago, when he suffered a shoulder injury. He underwent physical therapy but refused needed surgery because he lacked money and health insurance.

As the shoulder pain intensified, Mr. L quit his job. While out of work, he stopped attending physical therapy sessions when his depressive symptoms began to offset the shoulder pain. He suffered loss of concentration and motivation, increased fatigue with hypersomnia, and decreased appetite. He lost 10 to 12 lb in 1 year.

Mr. L also started having trouble “focusing on reality” and developed obsessive fears of malfunctions around the house, such as the furnace blowing up, the stove catching fire, or the toilet backing up. At one point, he began urinating and defecating in his pants to avoid using the toilet. He began to feel hopeless and several times tried to suffocate himself by placing a plastic bag over his head.

He also grew irritable, angry, and aggressive—mostly toward his wife, who increasingly feared him. He started blaming her for “everything wrong in my life” and began contemplating stabbing her to death or striking her head with a hammer.

 

Five months ago, Mr. L was involuntarily hospitalized for depressive symptoms, suicidality, and continued homicidal thoughts toward his wife. The attending psychiatrist started olanzapine, 5 mg nightly, for psychotic features, and citalopram, 10 mg/d, for depression and anxiety, and ordered one-on-one observation to prevent additional suicide attempts. Mr. L’s shoulder pain had resolved by this time.

Three days later, Mr. L began refusing to eat. The psychiatrist then increased citalopram to 20 mg/d and olanzapine to 5 mg bid and asked a hospital internist to evaluate for malnutrition and a psychologist to gauge cognitive and intellectual function.

During the psychologist’s evaluation, Mr. L showed average global intellectual functioning but delays in visual-motor speed, visual working memory, and alertness to his environment. These findings, however, did not explain the patient’s lower functioning at home or in the hospital.

We ruled out organic causes for Mr. L’s cognitive deficits after receiving normal brain MRI, urinalysis, rapid plasma reagin titer, and thyroid-stimulating hormone test results. We also ruled out malnutrition because vitamin B12 and folate levels were normal but ordered a dietary consult to help Mr. L regain weight.

Staff and family registered Mr. L for Medicare and Medicaid benefits so that he could become more independent, but his behavior soon regressed. He complained that staff and family were ignoring him and started urinating outside the bathroom, eating and smearing his feces, and bothering other patients. Staff directed Mr. L’s wife to ignore his verbal abuse over the phone and encourage him to stay motivated for treatment.

Mr. L’s disruptive behavior stopped after the psychologist tried individual therapy with behavior modification. The psychologist helped him devise a cleanliness plan and encouraged him to express his anger verbally rather than acting out. When Mr. L smeared his feces, he was to scrub the area with soap and water, take a 5-minute cold shower, put on clean clothes, and write and read an apology to hospital staff.

DISCHARGE: Nowhere to go

One month after admission, Mr. L was free of suicidal and homicidal thoughts and other symptoms. Staff prepared him for discharge, but his wife was contemplating divorce and refused to allow him back home. He also declined community outpatient treatment because he wanted his life to return to “normal” and was unaware that he was harming himself and others.

With no other disposition options, we discharged Mr. L to a homeless shelter. Later that day, shelter staff brought him back to the ER after they found him banging his head against an iron gate. We readmitted him to the psychiatric unit, at which point he endorsed suicidal thinking.

READMISSION: ‘Cold’ case

During this second hospitalization, Mr. L was again eating his feces as well as coloring himself with green markers, writing obscenities on the wall, and tearing up other patients’ papers. He repeatedly took 15-minute cold showers and told staff as they urged him out of the shower that he wanted to die by inducing hypothermia. During these episodes, he often called his estranged wife and told her what he was doing.

After the treatment team had Mr. L civilly committed, the attending psychiatrist titrated citalopram to 60 mg/d, discontinued olanzapine, and added aripiprazole to target the patient’s underlying depressive symptoms. Aripiprazole was started at 5 mg nightly and eventually titrated to 10 mg nightly. On 3 occasions during the month-long hospitalization, Mr. L refused to take his medications because he felt he did not belong in the hospital.

The attending psychiatrist diagnosed “dependent, passive-aggressive behaviors” and noted that Mr. L was “not amenable” to psychiatric hospitalization. The treatment team and outpatient community mental health department decided the patient had a personality disorder and that continued hospitalization would prevent him from attaining autonomy.

We then discharged Mr. L to a nursing home. There, he demanded a transfer back to the hospital or to jail because he feared he could not afford nursing home care and believed he could receive more attention elsewhere. His request was rejected after our ER psychiatrist found him medically and mentally fit to stay at the nursing home.

About 1 month later, Mr. L tried to smother a female patient by holding a pillow over her face but stopped when she began to struggle. After he told the nurses what he had done, staff immediately called police, who arrested Mr. L and transferred him to the county jail.

Because police and nursing home staff viewed the incident as a cry for help rather than a cold-blooded attack, police charged Mr. L with disorderly conduct. One month later, police dropped the charge and released him to the streets.

 

The authors’ observations

Mr. L triggered hateful reactions among several treatment team members, many of whom felt vindicated by his arrest. Clinicians might react this way if they feel a patient is wasting their time, manipulating them, not recognizing their narcissistic need for the patient to change, or ignoring their treatment plans.¹

Acknowledging the staff’s—and your own—reaction to a difficult patient is critical. Not doing so can lead to treatment decisions based on emotions rather than evidence. In a busy clinical setting, it’s easy to lose sight of this.

The following strategies can help you manage hateful countertransference, cope with a patient’s offensive behaviors, and make appropriate decisions:

• Allow staff members to discuss their feelings. Encourage them to acknowledge and discuss their feelings during team meetings or daily treatment discussions. This helped members of our team recognize that their identification with Mr. L’s self-rejection fueled their desire to “reject” him by discharging him to police or the homeless shelter.
  
• Joke about the patient’s behavior when appropriate. Humor is a mature and potentially healing defense mechanism. When not treating Mr. L, for example, we joked among ourselves about publishing a case report titled, “The case of the poop-eater.” Never joke about the patient in the therapeutic milieu, where it can be disruptive.
  
• See the behavior as a defense mechanism. Viewing patients’ reactions as defense mechanisms—rather than effects of a psychiatric disorder—can help you better understand the patient’s underlying pathophysiology.
  

READMISSION: More bad behavior

After his 3 arrests for public nudity, we readmit Mr. L, restart citalopram at 20 mg/d, and titrate it back to 60 mg/d to target his depression. We also switch back to olanzapine, 10 mg nightly, because the patient has seen little clinical benefit from aripiprazole and feels that olanzapine had improved his sleep.

In the psychiatric ward, Mr. L is once again disturbing patients, smearing and eating feces, and making half-hearted suicide attempts. Upset that staff is “ignoring” him, he enters other patients’ rooms without invitation and urinates in places other than the bathroom.

The authors’ observations

After 3 hospital admissions, Mr. L’s diagnosis remained unclear (Table 2). At his first admission, his symptoms suggested major depression with psychotic features. With his subsequent behaviors in the inpatient psychiatric unit—including primitive suicide attempts and smearing and eating feces—Mr. L showed a strong desire to be cared for. This and his past dependence on his wife and mother suggested a severe dependent personality disorder.

At his first discharge, Mr. L was diagnosed with a personality disorder with significant passive-aggressive traits. His lifelong dysphoria and lack of ambition also suggested dysthymia.

With discharge from this latest hospitalization pending, we searched for options. We considered Mr. L’s ongoing suicidality, persistent acting out, and aggression. Treatment team members discussed his use of “primitive defenses”² stemming from his limited coping skills in the face of severe depression.

Table 2

Mr. L’s differential diagnosis

Possible diagnosis	Mr. L’s symptoms
Major depression	Diminished motivation, concentration, and appetite Increased fatigue, hypersomnia Suicidal thinking
Personality disorder	Primitive, dependent behaviors Abnormal dependence on wife, mother
Depression with psychotic features	Depressive symptoms with obsessive suicidal/homicidal thoughts, fears of household malfunctions

TREATMENT: A different course

One week after admission, Mr. L’s inpatient psychiatrist recommends electroconvulsive therapy (ECT) to target the patient’s presumed severe depressive episodes and disruptive behaviors. The psychiatrist is experienced in performing ECT, which in clinical trials³ has shown efficacy in treatment-refractory major depression.

After giving informed consent, Mr. L receives 8 bilateral ECT treatments in 3 weeks. Also, the hospital psychologist performs behavioral modification similar to the previous cleanliness plan and again encourages Mr. L to express his anger and anxiety verbally.

By the second week of ECT, Mr. L’s disruptive behaviors have ceased. By the end of week 3, his mood and motivation have improved to the point where he shows interest in becoming independent. He says he wants to show his estranged wife he can care for himself and eventually reunite with her.

As Mr. L continues to improve, we discharge him to outpatient community mental health services and continue citalopram, 60 mg/d, and olanzapine, 5 mg nightly.

Nearly 2 years later, Mr. L is living independently. He has been regularly seeing his psychiatrist at the community mental health center and is maintained on citalopram and olanzapine. He continues trying to make amends with his wife but is still out of work and receives Social Security disability benefits.

The authors’ observations

Mr. L was fortunate that his inpatient psychiatrist could re-evaluate the diagnosis after identifying the staff’s significantly hateful countertransference. This allowed staff to offer ECT, which—despite its documented efficacy for major depression—is not widely available in the United States.

 

If no ECT providers were available, we would have considered medication change and long-term treatment in a state mental hospital until Mr. L showed he could care for himself.

Related resources

• Nagera H. Countertransference (PowerPoint presentation). Tampa, FL: The Carter Jenkins Center; 2003. www.thecjc.org/ppoint/ppoint/ct.ppt.
  
• MayoClinic.com video: Electroconvulsive therapy (ECT): One woman’s journey. Click on “Video” at top, then scroll to title.
  

Drug brand names

• Aripiprazole • Abilify
  
• Olanzapine • Zyprexa
  
• Citalopram • Celexa
  

Disclosure

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

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.

Some schizophrenia patients have shown significant improvements in positive and negative symptoms when my colleagues and I added acetylcholinesterase inhibitors (AChEIs) to their anti-psychotic regimens. We cannot rule out these benefits as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefited from AChEIs but stopped them, the benefits rapidly disappeared. Then, when these patients restarted the medications, the benefits recurred.

Unfortunately, recent well-controlled clinical studies have not supported these anecdotal findings or the results of approximately 20 preliminary trials. Thus, this article explains:

• why we don’t recommend using off-label AChEIs as a “first choice” augmentation strategy in schizophrenia patients at this time
  
• under what circumstances the adjunctive use of these agents might be reasonable.
  

Why Alzheimer’s medications?

Schizophrenia and Alzheimer’s disease (AD) have dramatically different onset, symptoms, course, and pathophysiology. As reviewed below, schizophrenia patients are no more likely to develop AD than the general population, and AChEIs—even when effective—have a short-term, limited benefit in AD.

So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with the intriguing effects of cholinergic agents on cognition.

Toward cognitive enhancement

Schizophrenia’s cognitive impairments may occur at a very early age, often before other overt symptoms,¹ then may worsen—sometimes to dementia levels—when obvious psychotic symptoms emerge.²

Positive symptoms (hallucinations, delusions, thought disorder, etc.) and—to a lesser extent—negative symptoms (anhedonia, asociality, blunted affect, etc.) often improve when patients are treated with antipsychotics. Antipsychotics do not significantly improve cognitive symptoms (attention, reaction time, working memory, verbal fluency, etc.), however, and cognitive symptoms are the strongest predictors of poor functional outcomes in our patients.

Heterogeneous disorder. In 2000, Cummings³ summarized evidence from case re-ports and small studies that AChEIs were useful in treating neuropsychiatric conditions other than AD (Table 1). Cholinergic agents, Cummings noted, “affect many aspects of cognition, which suggests that the primary effect may be on an attentional or executive system with a secondary, pan-intellectual modulating influence on memory, language, and visuospatial skills.”⁴

In schizophrenia, different patients have different types of cognitive impairment.⁵ Thus, broad-based cognitive enhancers such as AChEIs may be necessary for general use in this illness.

Acetyltransferase activity. Schizophrenia patients—even those meeting criteria for dementia—do not usually have typical AD neuropathology, and the incidence of AD is no different in elderly patients with or without comorbid schizophrenia.⁶ At autopsy, schizophrenia patients and normal controls have similar brain cortical choline acetyltransferase levels.

Nevertheless, persons with AD and those with schizophrenia show a similar, statistically significant negative correlation between premorbid Clinical Dementia Rating scale scores and brain cortical choline acetyltransferase activity (r=– 0.36, P 6 Furthermore, studies have found cholinergic neurotransmission alterations in schizophrenia patients, including:

• a deficit in regulation of the low-affinity alpha-7 nicotinic receptor in those with impaired sensory gating⁷
  
• altered high-affinity nicotinic receptor binding⁸
  
• decreased hippocampal muscarinic receptor binding compared with matched normal controls⁹
  
• reduced density of cholinergic inter-neurons in the ventral striatum.¹⁰
  

These findings—plus the presumably “nonspecific” benefits of AChEIs in many illnesses³—suggest that some patients with schizophrenia may have deficits in nicotinic and/or muscarinic cholinergic neurophysiology, which might be amenable to pharmacologic supplementation.

Table 1

Cholinesterase inhibitors have shown benefit in many neuropsychiatric conditions*

Alcoholism with Wernicke’s encephalopathy
Attention-deficit/hyperactivity disorder
Autism
Bipolar disorder
Creutzfeldt-Jakob disease
Dementia pugilistica
Dementia with Lewy bodies
Olivopontocerebellar atrophy
Parkinson’s disease with dementia
Parkinsonism dementia complex of Guam
Pick’s disease
Progressive supranuclear palsy
Schizophrenia
Sleep disorders
Subacute sclerosing panencephalitis
Traumatic brain injury
Vascular dementia
* Data from case reports and small studies. Cholinesterase inhibitors are FDA-approved only for Alzheimer’s dementia.
Source: Reference 3

AChEI augmentation

Mixed results. A number of investigators—including myself—have published data indicating that adding AChEIs—most often donepezil, but also rivastigmine or galantamine—to antipsychotic regimens may improve some schizophrenia patients’ symptoms and general functioning. These benefits were modest, however, when they were seen in these relatively small case reports and studies (Box).

Box

 

Other studies of AChEI augmentation of typical or atypical antipsychotics have been:

• equivocal, reporting benefits in some but not all patients (with no clear statistical or clinical conclusions) or in schizophrenia patients with comorbid dementia^11-14
  
• decisively negative, showing no benefits, particularly in comparatively larger, randomized, placebo-controlled trials (Table 2).^15-19
  

Meta-analysis power. In an attempt to understand these wide-ranging results, Chouinard et al²⁰ performed an elegant meta-analysis of oral AChEI augmentation therapies for cognitive enhancement in schizophrenia. This review emphasized the available studies’ complexity, small number and sample sizes, and small benefit effect sizes.

The authors concluded that—based on preliminary data—adjunctive AChEIs seemed to have “some beneficial effects” on attention and memory for schizophrenia patients.

The last word? Within weeks, however, results of a large multicenter trial by Keefe et al²¹ showed that donepezil augmentation was no more effective than placebo in improving cognition in patients with schizophrenia or schizoaffective disorder. In this 38-center, randomized, double-blind, placebo-controlled, parallel design study, 250 patients with mild to moderate cognitive impairment received adjunctive donepezil—5 mg/d for 6 weeks, then 10 mg/d for 6 weeks—or placebo for 12 weeks.

Both the treatment and placebo groups experienced statistically and clinically significant benefits from baseline in measures of cognition, positive symptoms, and negative symptoms. For all measures, placebo augmentation was equal to or superior to donepezil augmentation.

Table 2

Controlled trials: No benefit from AChEIs in schizophrenia

Study design	Subjects	Drug (dosage)	Results
Friedman et al (2002),15 double-blind, placebo-controlled	36 patients with schizophrenia	Donepezil, 5 or 10 mg/d for 12 weeks	Neither dose produced significant improvement in any cognitive measure
Tugal et al (2004),16 double-blind, placebo- controlled, crossover	12 patients with stable schizophrenia	Donepezil, 5 mg/d for 6 weeks, with crossover to placebo for 6 weeks	Treatment effect was not significant in any cognitive measure
Freudenreich et al (2005),17 double-blind, placebo-controlled	36 stable outpatients with schizophrenia	Donepezil, ≤10 mg/d for 8 weeks	No improvement in cognition or psychopathology measures
Sharma et al (2006),18 randomized, double-blind, placebo-controlled	21 patients with stable schizophrenia	Rivastigmine, 12 mg/d for 24 weeks	No significant improvement in any cognitive measure
Fagerlund et al (2007),19 double-blind, placebo-controlled	21 patients enrolled, 11 completed	Donepezil, 5 or 10 mg/d for 4 months added to ziprasidone	No differences in changes on PANSS scores or a global cognitive score
Keefe et al (2007),21 randomized, double-blind, placebo-controlled	250 stable outpatients with schizophrenia or schizoaffective disorder	Donepezil, 5 mg for 6 weeks then 10 mg for 6 weeks	Donepezil was well-tolerated but did not improve cognition any more than placebo
PANSS: Positive and Negative Syndrome Scale

Analyzing trial results

The large, well-designed clinical trial by Keefe et al²¹ suggests conclusively that donepezil augmentation is not more effective than placebo in most stable schizophrenia or schizoaffective disorder patients with mild to moderate cognitive impairment.

Even so, it is arguably difficult to “prove a negative.” For example:

• Different dosages might have been more effective.
  
• Longer treatment (>3 months) might have been necessary for donepezil to “surpass” the large placebo effect.
  
• Other AChEIs—such as galantamine, which stimulates nicotinic receptors—might be more effective than donepezil, which is predominantly muscarinic.
  

‘Subgroup’ hypothesis. Finally, if schizophrenia’s pathophysiology is extremely heterogeneous, AChEI augmentation might benefit only the small subgroup of patients with decreased cholinergic activity. Most other patients—without decreased cholinergic activity—would not benefit or might even worsen. In support of the “subgroup” hypothesis, Miller²² has reported that many augmentation agents have efficacy in schizophrenia—but only in a minority of patients.

If this hypothesis is true, clinicians would need to differentiate patients before giving them trials of AChEIs or other augmentation therapies. Genetic testing might identify different pathophysiologies among patients, but these technologies are not yet clinically available.

Recommendations

Clinical experience, case reports, and small case series indicate that occasional patients may benefit from AChEI augmentation. On the other hand, the only large, multi-center, placebo-controlled, parallel-design study found no difference between donepezil and placebo augmentation of atypical antipsychotics.²¹

Thus this review of available evidence does not support the routine use of AChEI augmentation of typical or atypical antipsychotics as a viable psychopharmacologic strategy. Until more supportive evidence has been reported, this reviewer cannot recommend AChEIs as a “first line” augmentation strategy. Furthermore, because these medications do not have an FDA-approved indication in schizophrenia and are expensive, a cost-benefit appraisal also would not support their routine use.

Nevertheless, AChEIs are relatively safe and occasionally have been dramatically effective in a small subgroup of schizophrenia patients when used as augmentation. They may represent a reasonable approach:

 

• when other adjuncts have failed
  
• as a supplement to other augmentation strategies, such as cognitive-behavioral therapy or family therapy.
  

Related resources

• Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deficits in schizophrenia. Arch Gen Psychiatry 1999;56:749-54.
  
• Risch SC, Horner MD, McGurk S, et al. Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res 2007;93:131-5.
  

Drug brand names

• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Reminyl, Razadyne
  
• Ziprasidone • Geodon
  

Disclosure

Dr. Risch receives research support from the National Institute of Mental Health, Abbott Laboratories, GlaxoSmithKline, Bristol-Myers Squibb, and Forest Pharmaceuticals. He is a consultant to and speaker for AstraZeneca and Pfizer Inc.

Some schizophrenia patients have shown significant improvements in positive and negative symptoms when my colleagues and I added acetylcholinesterase inhibitors (AChEIs) to their anti-psychotic regimens. We cannot rule out these benefits as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefited from AChEIs but stopped them, the benefits rapidly disappeared. Then, when these patients restarted the medications, the benefits recurred.

Unfortunately, recent well-controlled clinical studies have not supported these anecdotal findings or the results of approximately 20 preliminary trials. Thus, this article explains:

• why we don’t recommend using off-label AChEIs as a “first choice” augmentation strategy in schizophrenia patients at this time
  
• under what circumstances the adjunctive use of these agents might be reasonable.
  

Why Alzheimer’s medications?

Schizophrenia and Alzheimer’s disease (AD) have dramatically different onset, symptoms, course, and pathophysiology. As reviewed below, schizophrenia patients are no more likely to develop AD than the general population, and AChEIs—even when effective—have a short-term, limited benefit in AD.

So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with the intriguing effects of cholinergic agents on cognition.

Toward cognitive enhancement

Schizophrenia’s cognitive impairments may occur at a very early age, often before other overt symptoms,¹ then may worsen—sometimes to dementia levels—when obvious psychotic symptoms emerge.²

Positive symptoms (hallucinations, delusions, thought disorder, etc.) and—to a lesser extent—negative symptoms (anhedonia, asociality, blunted affect, etc.) often improve when patients are treated with antipsychotics. Antipsychotics do not significantly improve cognitive symptoms (attention, reaction time, working memory, verbal fluency, etc.), however, and cognitive symptoms are the strongest predictors of poor functional outcomes in our patients.

Heterogeneous disorder. In 2000, Cummings³ summarized evidence from case re-ports and small studies that AChEIs were useful in treating neuropsychiatric conditions other than AD (Table 1). Cholinergic agents, Cummings noted, “affect many aspects of cognition, which suggests that the primary effect may be on an attentional or executive system with a secondary, pan-intellectual modulating influence on memory, language, and visuospatial skills.”⁴

In schizophrenia, different patients have different types of cognitive impairment.⁵ Thus, broad-based cognitive enhancers such as AChEIs may be necessary for general use in this illness.

Acetyltransferase activity. Schizophrenia patients—even those meeting criteria for dementia—do not usually have typical AD neuropathology, and the incidence of AD is no different in elderly patients with or without comorbid schizophrenia.⁶ At autopsy, schizophrenia patients and normal controls have similar brain cortical choline acetyltransferase levels.

Nevertheless, persons with AD and those with schizophrenia show a similar, statistically significant negative correlation between premorbid Clinical Dementia Rating scale scores and brain cortical choline acetyltransferase activity (r=– 0.36, P 6 Furthermore, studies have found cholinergic neurotransmission alterations in schizophrenia patients, including:

• a deficit in regulation of the low-affinity alpha-7 nicotinic receptor in those with impaired sensory gating⁷
  
• altered high-affinity nicotinic receptor binding⁸
  
• decreased hippocampal muscarinic receptor binding compared with matched normal controls⁹
  
• reduced density of cholinergic inter-neurons in the ventral striatum.¹⁰
  

These findings—plus the presumably “nonspecific” benefits of AChEIs in many illnesses³—suggest that some patients with schizophrenia may have deficits in nicotinic and/or muscarinic cholinergic neurophysiology, which might be amenable to pharmacologic supplementation.

Table 1

Cholinesterase inhibitors have shown benefit in many neuropsychiatric conditions*

Alcoholism with Wernicke’s encephalopathy
Attention-deficit/hyperactivity disorder
Autism
Bipolar disorder
Creutzfeldt-Jakob disease
Dementia pugilistica
Dementia with Lewy bodies
Olivopontocerebellar atrophy
Parkinson’s disease with dementia
Parkinsonism dementia complex of Guam
Pick’s disease
Progressive supranuclear palsy
Schizophrenia
Sleep disorders
Subacute sclerosing panencephalitis
Traumatic brain injury
Vascular dementia
* Data from case reports and small studies. Cholinesterase inhibitors are FDA-approved only for Alzheimer’s dementia.
Source: Reference 3

AChEI augmentation

Mixed results. A number of investigators—including myself—have published data indicating that adding AChEIs—most often donepezil, but also rivastigmine or galantamine—to antipsychotic regimens may improve some schizophrenia patients’ symptoms and general functioning. These benefits were modest, however, when they were seen in these relatively small case reports and studies (Box).

Box

 

Other studies of AChEI augmentation of typical or atypical antipsychotics have been:

• equivocal, reporting benefits in some but not all patients (with no clear statistical or clinical conclusions) or in schizophrenia patients with comorbid dementia^11-14
  
• decisively negative, showing no benefits, particularly in comparatively larger, randomized, placebo-controlled trials (Table 2).^15-19
  

Meta-analysis power. In an attempt to understand these wide-ranging results, Chouinard et al²⁰ performed an elegant meta-analysis of oral AChEI augmentation therapies for cognitive enhancement in schizophrenia. This review emphasized the available studies’ complexity, small number and sample sizes, and small benefit effect sizes.

The authors concluded that—based on preliminary data—adjunctive AChEIs seemed to have “some beneficial effects” on attention and memory for schizophrenia patients.

The last word? Within weeks, however, results of a large multicenter trial by Keefe et al²¹ showed that donepezil augmentation was no more effective than placebo in improving cognition in patients with schizophrenia or schizoaffective disorder. In this 38-center, randomized, double-blind, placebo-controlled, parallel design study, 250 patients with mild to moderate cognitive impairment received adjunctive donepezil—5 mg/d for 6 weeks, then 10 mg/d for 6 weeks—or placebo for 12 weeks.

Both the treatment and placebo groups experienced statistically and clinically significant benefits from baseline in measures of cognition, positive symptoms, and negative symptoms. For all measures, placebo augmentation was equal to or superior to donepezil augmentation.

Table 2

Controlled trials: No benefit from AChEIs in schizophrenia

Study design	Subjects	Drug (dosage)	Results
Friedman et al (2002),15 double-blind, placebo-controlled	36 patients with schizophrenia	Donepezil, 5 or 10 mg/d for 12 weeks	Neither dose produced significant improvement in any cognitive measure
Tugal et al (2004),16 double-blind, placebo- controlled, crossover	12 patients with stable schizophrenia	Donepezil, 5 mg/d for 6 weeks, with crossover to placebo for 6 weeks	Treatment effect was not significant in any cognitive measure
Freudenreich et al (2005),17 double-blind, placebo-controlled	36 stable outpatients with schizophrenia	Donepezil, ≤10 mg/d for 8 weeks	No improvement in cognition or psychopathology measures
Sharma et al (2006),18 randomized, double-blind, placebo-controlled	21 patients with stable schizophrenia	Rivastigmine, 12 mg/d for 24 weeks	No significant improvement in any cognitive measure
Fagerlund et al (2007),19 double-blind, placebo-controlled	21 patients enrolled, 11 completed	Donepezil, 5 or 10 mg/d for 4 months added to ziprasidone	No differences in changes on PANSS scores or a global cognitive score
Keefe et al (2007),21 randomized, double-blind, placebo-controlled	250 stable outpatients with schizophrenia or schizoaffective disorder	Donepezil, 5 mg for 6 weeks then 10 mg for 6 weeks	Donepezil was well-tolerated but did not improve cognition any more than placebo
PANSS: Positive and Negative Syndrome Scale

Analyzing trial results

The large, well-designed clinical trial by Keefe et al²¹ suggests conclusively that donepezil augmentation is not more effective than placebo in most stable schizophrenia or schizoaffective disorder patients with mild to moderate cognitive impairment.

Even so, it is arguably difficult to “prove a negative.” For example:

• Different dosages might have been more effective.
  
• Longer treatment (>3 months) might have been necessary for donepezil to “surpass” the large placebo effect.
  
• Other AChEIs—such as galantamine, which stimulates nicotinic receptors—might be more effective than donepezil, which is predominantly muscarinic.
  

‘Subgroup’ hypothesis. Finally, if schizophrenia’s pathophysiology is extremely heterogeneous, AChEI augmentation might benefit only the small subgroup of patients with decreased cholinergic activity. Most other patients—without decreased cholinergic activity—would not benefit or might even worsen. In support of the “subgroup” hypothesis, Miller²² has reported that many augmentation agents have efficacy in schizophrenia—but only in a minority of patients.

If this hypothesis is true, clinicians would need to differentiate patients before giving them trials of AChEIs or other augmentation therapies. Genetic testing might identify different pathophysiologies among patients, but these technologies are not yet clinically available.

Recommendations

Clinical experience, case reports, and small case series indicate that occasional patients may benefit from AChEI augmentation. On the other hand, the only large, multi-center, placebo-controlled, parallel-design study found no difference between donepezil and placebo augmentation of atypical antipsychotics.²¹

Thus this review of available evidence does not support the routine use of AChEI augmentation of typical or atypical antipsychotics as a viable psychopharmacologic strategy. Until more supportive evidence has been reported, this reviewer cannot recommend AChEIs as a “first line” augmentation strategy. Furthermore, because these medications do not have an FDA-approved indication in schizophrenia and are expensive, a cost-benefit appraisal also would not support their routine use.

Nevertheless, AChEIs are relatively safe and occasionally have been dramatically effective in a small subgroup of schizophrenia patients when used as augmentation. They may represent a reasonable approach:

 

• when other adjuncts have failed
  
• as a supplement to other augmentation strategies, such as cognitive-behavioral therapy or family therapy.
  

Related resources

• Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deficits in schizophrenia. Arch Gen Psychiatry 1999;56:749-54.
  
• Risch SC, Horner MD, McGurk S, et al. Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res 2007;93:131-5.
  

Drug brand names

• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Reminyl, Razadyne
  
• Ziprasidone • Geodon
  

Disclosure

Dr. Risch receives research support from the National Institute of Mental Health, Abbott Laboratories, GlaxoSmithKline, Bristol-Myers Squibb, and Forest Pharmaceuticals. He is a consultant to and speaker for AstraZeneca and Pfizer Inc.

Some schizophrenia patients have shown significant improvements in positive and negative symptoms when my colleagues and I added acetylcholinesterase inhibitors (AChEIs) to their anti-psychotic regimens. We cannot rule out these benefits as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefited from AChEIs but stopped them, the benefits rapidly disappeared. Then, when these patients restarted the medications, the benefits recurred.

Unfortunately, recent well-controlled clinical studies have not supported these anecdotal findings or the results of approximately 20 preliminary trials. Thus, this article explains:

• why we don’t recommend using off-label AChEIs as a “first choice” augmentation strategy in schizophrenia patients at this time
  
• under what circumstances the adjunctive use of these agents might be reasonable.
  

Why Alzheimer’s medications?

Schizophrenia and Alzheimer’s disease (AD) have dramatically different onset, symptoms, course, and pathophysiology. As reviewed below, schizophrenia patients are no more likely to develop AD than the general population, and AChEIs—even when effective—have a short-term, limited benefit in AD.

So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with the intriguing effects of cholinergic agents on cognition.

Toward cognitive enhancement

Schizophrenia’s cognitive impairments may occur at a very early age, often before other overt symptoms,¹ then may worsen—sometimes to dementia levels—when obvious psychotic symptoms emerge.²

Positive symptoms (hallucinations, delusions, thought disorder, etc.) and—to a lesser extent—negative symptoms (anhedonia, asociality, blunted affect, etc.) often improve when patients are treated with antipsychotics. Antipsychotics do not significantly improve cognitive symptoms (attention, reaction time, working memory, verbal fluency, etc.), however, and cognitive symptoms are the strongest predictors of poor functional outcomes in our patients.

Heterogeneous disorder. In 2000, Cummings³ summarized evidence from case re-ports and small studies that AChEIs were useful in treating neuropsychiatric conditions other than AD (Table 1). Cholinergic agents, Cummings noted, “affect many aspects of cognition, which suggests that the primary effect may be on an attentional or executive system with a secondary, pan-intellectual modulating influence on memory, language, and visuospatial skills.”⁴

In schizophrenia, different patients have different types of cognitive impairment.⁵ Thus, broad-based cognitive enhancers such as AChEIs may be necessary for general use in this illness.

Acetyltransferase activity. Schizophrenia patients—even those meeting criteria for dementia—do not usually have typical AD neuropathology, and the incidence of AD is no different in elderly patients with or without comorbid schizophrenia.⁶ At autopsy, schizophrenia patients and normal controls have similar brain cortical choline acetyltransferase levels.

Nevertheless, persons with AD and those with schizophrenia show a similar, statistically significant negative correlation between premorbid Clinical Dementia Rating scale scores and brain cortical choline acetyltransferase activity (r=– 0.36, P 6 Furthermore, studies have found cholinergic neurotransmission alterations in schizophrenia patients, including:

• a deficit in regulation of the low-affinity alpha-7 nicotinic receptor in those with impaired sensory gating⁷
  
• altered high-affinity nicotinic receptor binding⁸
  
• decreased hippocampal muscarinic receptor binding compared with matched normal controls⁹
  
• reduced density of cholinergic inter-neurons in the ventral striatum.¹⁰
  

These findings—plus the presumably “nonspecific” benefits of AChEIs in many illnesses³—suggest that some patients with schizophrenia may have deficits in nicotinic and/or muscarinic cholinergic neurophysiology, which might be amenable to pharmacologic supplementation.

Table 1

Cholinesterase inhibitors have shown benefit in many neuropsychiatric conditions*

Alcoholism with Wernicke’s encephalopathy
Attention-deficit/hyperactivity disorder
Autism
Bipolar disorder
Creutzfeldt-Jakob disease
Dementia pugilistica
Dementia with Lewy bodies
Olivopontocerebellar atrophy
Parkinson’s disease with dementia
Parkinsonism dementia complex of Guam
Pick’s disease
Progressive supranuclear palsy
Schizophrenia
Sleep disorders
Subacute sclerosing panencephalitis
Traumatic brain injury
Vascular dementia
* Data from case reports and small studies. Cholinesterase inhibitors are FDA-approved only for Alzheimer’s dementia.
Source: Reference 3

AChEI augmentation

Mixed results. A number of investigators—including myself—have published data indicating that adding AChEIs—most often donepezil, but also rivastigmine or galantamine—to antipsychotic regimens may improve some schizophrenia patients’ symptoms and general functioning. These benefits were modest, however, when they were seen in these relatively small case reports and studies (Box).

Box

 

Other studies of AChEI augmentation of typical or atypical antipsychotics have been:

• equivocal, reporting benefits in some but not all patients (with no clear statistical or clinical conclusions) or in schizophrenia patients with comorbid dementia^11-14
  
• decisively negative, showing no benefits, particularly in comparatively larger, randomized, placebo-controlled trials (Table 2).^15-19
  

Meta-analysis power. In an attempt to understand these wide-ranging results, Chouinard et al²⁰ performed an elegant meta-analysis of oral AChEI augmentation therapies for cognitive enhancement in schizophrenia. This review emphasized the available studies’ complexity, small number and sample sizes, and small benefit effect sizes.

The authors concluded that—based on preliminary data—adjunctive AChEIs seemed to have “some beneficial effects” on attention and memory for schizophrenia patients.

The last word? Within weeks, however, results of a large multicenter trial by Keefe et al²¹ showed that donepezil augmentation was no more effective than placebo in improving cognition in patients with schizophrenia or schizoaffective disorder. In this 38-center, randomized, double-blind, placebo-controlled, parallel design study, 250 patients with mild to moderate cognitive impairment received adjunctive donepezil—5 mg/d for 6 weeks, then 10 mg/d for 6 weeks—or placebo for 12 weeks.

Both the treatment and placebo groups experienced statistically and clinically significant benefits from baseline in measures of cognition, positive symptoms, and negative symptoms. For all measures, placebo augmentation was equal to or superior to donepezil augmentation.

Table 2

Controlled trials: No benefit from AChEIs in schizophrenia

Study design	Subjects	Drug (dosage)	Results
Friedman et al (2002),15 double-blind, placebo-controlled	36 patients with schizophrenia	Donepezil, 5 or 10 mg/d for 12 weeks	Neither dose produced significant improvement in any cognitive measure
Tugal et al (2004),16 double-blind, placebo- controlled, crossover	12 patients with stable schizophrenia	Donepezil, 5 mg/d for 6 weeks, with crossover to placebo for 6 weeks	Treatment effect was not significant in any cognitive measure
Freudenreich et al (2005),17 double-blind, placebo-controlled	36 stable outpatients with schizophrenia	Donepezil, ≤10 mg/d for 8 weeks	No improvement in cognition or psychopathology measures
Sharma et al (2006),18 randomized, double-blind, placebo-controlled	21 patients with stable schizophrenia	Rivastigmine, 12 mg/d for 24 weeks	No significant improvement in any cognitive measure
Fagerlund et al (2007),19 double-blind, placebo-controlled	21 patients enrolled, 11 completed	Donepezil, 5 or 10 mg/d for 4 months added to ziprasidone	No differences in changes on PANSS scores or a global cognitive score
Keefe et al (2007),21 randomized, double-blind, placebo-controlled	250 stable outpatients with schizophrenia or schizoaffective disorder	Donepezil, 5 mg for 6 weeks then 10 mg for 6 weeks	Donepezil was well-tolerated but did not improve cognition any more than placebo
PANSS: Positive and Negative Syndrome Scale

Analyzing trial results

The large, well-designed clinical trial by Keefe et al²¹ suggests conclusively that donepezil augmentation is not more effective than placebo in most stable schizophrenia or schizoaffective disorder patients with mild to moderate cognitive impairment.

Even so, it is arguably difficult to “prove a negative.” For example:

• Different dosages might have been more effective.
  
• Longer treatment (>3 months) might have been necessary for donepezil to “surpass” the large placebo effect.
  
• Other AChEIs—such as galantamine, which stimulates nicotinic receptors—might be more effective than donepezil, which is predominantly muscarinic.
  

‘Subgroup’ hypothesis. Finally, if schizophrenia’s pathophysiology is extremely heterogeneous, AChEI augmentation might benefit only the small subgroup of patients with decreased cholinergic activity. Most other patients—without decreased cholinergic activity—would not benefit or might even worsen. In support of the “subgroup” hypothesis, Miller²² has reported that many augmentation agents have efficacy in schizophrenia—but only in a minority of patients.

If this hypothesis is true, clinicians would need to differentiate patients before giving them trials of AChEIs or other augmentation therapies. Genetic testing might identify different pathophysiologies among patients, but these technologies are not yet clinically available.

Recommendations

Clinical experience, case reports, and small case series indicate that occasional patients may benefit from AChEI augmentation. On the other hand, the only large, multi-center, placebo-controlled, parallel-design study found no difference between donepezil and placebo augmentation of atypical antipsychotics.²¹

Thus this review of available evidence does not support the routine use of AChEI augmentation of typical or atypical antipsychotics as a viable psychopharmacologic strategy. Until more supportive evidence has been reported, this reviewer cannot recommend AChEIs as a “first line” augmentation strategy. Furthermore, because these medications do not have an FDA-approved indication in schizophrenia and are expensive, a cost-benefit appraisal also would not support their routine use.

Nevertheless, AChEIs are relatively safe and occasionally have been dramatically effective in a small subgroup of schizophrenia patients when used as augmentation. They may represent a reasonable approach:

 

• when other adjuncts have failed
  
• as a supplement to other augmentation strategies, such as cognitive-behavioral therapy or family therapy.
  

Related resources

• Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deficits in schizophrenia. Arch Gen Psychiatry 1999;56:749-54.
  
• Risch SC, Horner MD, McGurk S, et al. Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res 2007;93:131-5.
  

Drug brand names

• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Reminyl, Razadyne
  
• Ziprasidone • Geodon
  

Disclosure

Dr. Risch receives research support from the National Institute of Mental Health, Abbott Laboratories, GlaxoSmithKline, Bristol-Myers Squibb, and Forest Pharmaceuticals. He is a consultant to and speaker for AstraZeneca and Pfizer Inc.

Ms. W, a 73-year-old widow with no psychiatric history, visits her primary care physician because she is concerned about her memory. She denies impairment in other cognitive domains—such as executive function—or activities of daily living.

Ms. W relates prominent worries about her health and finances and those of her grandchildren. She describes daily restlessness, sleep-onset insomnia, difficulty concentrating, and mild episodic dysphoria. She says she’s always been a “worry wart” but her worry and other symptoms have become increasingly intrusive over the past 5 years with a series of deaths in her family. Ms. W’s medical history includes hypertension and type 2 diabetes. Unsure how to treat her, the physician refers Ms. W to a psychiatrist.

Older adults with anxiety symptoms often are dissatisfied with treatment because they believe they receive insufficient help. This complaint is probably valid because limited data support pharmacologic interventions for anxiety in older adults, and therapy is often based on inferences from studies in younger subjects. Moreover, many anxious older patients are treated with benzodiazepines, which increases their risk for cognitive impairment and injuries.^1,2

Fortunately, growing evidence points to 2 treatment modalities for anxiety disorders in patients age ≥65:

• pharmacotherapy with antidepressants, benzodiazepines, and (perhaps) buspirone
  
• cognitive-behavioral therapy (CBT) for generalized anxiety disorder (GAD), panic disorder (PD), and mixed anxiety syndromes.
  

A common, debilitating problem

Anxious older adults report diminished perceived health, physical activities, and quality of life and increased loneliness compared with their nonanxious counterparts.¹ The prevalence of anxiety disorders in older patients ranges from 0.4% for obsessive-compulsive disorder to 11.5% for GAD.³

Older adults with GAD present with a constellation of medical, psychiatric, psychological, and psychosocial features (Table 1).^1,3-12 Anxiety disorders in older adults also may co-occur with major depressive disorder, other psychiatric conditions, or dementia, which can complicate diagnosis and treatment.

Table 1

Is it GAD? Common features in older adults

Demographics
More prevalent at age
More common in women
Medical
Frequent visits to primary care
Low satisfaction with medical care
≥2 chronic physical illnesses
≥1 adaptive behavior limitations
Cognitive impairment, particularly verbal memory
Psychiatric
History of GAD symptoms (5 to ≥20 years)
Physiologic anxiety symptoms: restlessness, fatigue, muscle tension
Depressive symptoms
Prescribed a benzodiazepine
Presence of anxiety disorders
Suicidal ideation, particularly if depressed
Psychological
External locus of control
Neuroticism
Psychosocial
Limited social network
Perceived low instrumental support
Recent losses and traumatic life events
Loss of partner
GAD: generalized anxiety disorder
Source: References 1,3-12

CASE CONTINUED: Anxious, not depressed

You screen Ms. W with the Geriatric Depression Scale (short form; GDS) and Beck Anxiety Inventory (BAI). Her scores indicate no depression and moderate anxiousness. A neuropsychological screen finds no cognitive impairments. Based on the clinical interview and screening, Ms. W meets DSM-IV-TR criteria for GAD.

Psychopharmacologic interventions are first-line treatment for older adults with anxiety disorders, but you might consider other strategies because:

• Older patients may have increased vulnerability to medication side effects.
  
• Few randomized, placebo-controlled trials have examined psychopharmacologic interventions specifically for anxious older adults.
  

Evidence supports using psychotherapy as an alternative or adjunct to pharmacotherapy for treating anxiety symptoms. A meta-analysis of 15 studies that included 495 adults (mean age 69.5 years) with late-life anxiety symptoms and 20 psychotherapeutic interventions indicated that psychotherapy was reliably more effective than no treatment.¹³

First-line pharmacotherapies

When selecting pharmacotherapy for an older adult with anxiety, take into account:

• physiologic changes in drug metabolism (older patients metabolize drugs more slowly than younger patients)
  
• comorbid medical problems
  
• polypharmacy (many older patients are taking multiple medications for multiple conditions, which increases the risk of drug-drug interactions).
  

Also consider prior treatment response and symptom severity when choosing the medication you feel will be most tolerable. “Start low and go slow” to avoid side effects while titrating the medication to the optimal dosage (Table 2).

Pharmacologic management of anxiety typically has included benzodiazepines, tricyclic antidepressants, barbiturates, and antihistamines. Newer antidepressants have emerged as first-line treatment for several anxiety disorders and mixed anxiety-depression syndromes, however, because of their more tolerable side-effect profiles, especially when used long-term.¹⁴ These antidepressants include:

• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin/norepinephrine reuptake inhibitors (SNRIs).
  

SSRIs are useful for treating anxiety disorders in young and middle-aged adults, as shown in randomized, placebo-controlled clinical trials. Much less evidence exists, however, on the use of SSRIs in anxious older adults.

Citalopram—started at 10 mg/d and titrated to 30 mg/d as tolerated—was used in the only prospective, double-blind, randomized, controlled trial of an SSRI in older patients with anxiety disorders. In this 8-week trial, Clinical Global Impression scale scores and Hamilton Anxiety scale scores improved.¹⁵ In other investigations:

 

• Paroxetine, averaging approximately 28 mg/d, produced a similar response in older and younger adults with PD in terms of efficacy and tolerability in a naturalistic follow-up trial.¹⁶
  
• Sertraline, started at 25 mg/d and titrated to 100 mg/d (maximum 150 mg/d), when combined with CBT was effective for treating older adults with anxiety disorders in a randomized, placebo-controlled trial¹⁷ and specifically for those with PD in an open-label trial.¹⁸
  
• Fluvoxamine, median 200 mg/d, reduced anxiety symptoms in an open-label study of 12 older adults with various anxiety disorders. Most patients with GAD (57%) responded to fluvoxamine, but 3 patients with PD did not.¹⁹
  
• We found no studies of fluoxetine for anxiety symptoms in older adults.
  

An important caveat to these findings is data suggesting older adults with mixed anxiety and depression (MAD) may take longer to respond to pharmacologic and psychotherapeutic interventions than older adults with anxiety or depression alone.^20,21 On the other hand, Lenze et al²² found no evidence of a lower or slower response to paroxetine in depressed older adults with or without anxiety. In an open-label, flexible-dose study, escitalopram, 10 to 20 mg/ d, reduced comorbid anxiety and depression symptoms and improved social functioning in 17 older outpatients.²³

SNRIs. In a retrospective, pooled analysis of 5 randomized, placebo-controlled trials²⁴ venlafaxine ER, 37.5 to 225 mg/d, was significantly more effective than placebo in treating older adults with GAD. Several studies suggest duloxetine may be effective for treating GAD in adults, but none examined efficacy specifically for older adults.

Benzodiazepines’ primary benefits are rapid onset and minimal cardiovascular effects. They remain the mainstay of pharmacologic therapy for acute anxiety and can be useful as initial, short-term adjunctive therapy with SSRIs and SNRIs.

Using benzodiazepines for more than a few weeks in older adults is not recommended, however.¹⁴ Potential complications of long-term benzodiazepine use in these patients include:

• excessive daytime drowsiness
  
• cognitive and psychomotor impairment
  
• confusion
  
• risk of falls
  
• depression
  
• paradoxical reactions
  
• amnesic syndromes
  
• respiratory problems
  
• potential for abuse/dependence
  
• breakthrough withdrawal reactions.^2,25,26
  

For older patients, short half-life benzodiazepines—such as lorazepam (maximum 1 to 3 mg/d divided bid or tid) or oxazepam (maximum 45 to 60 mg/d divided tid or qid)—are preferred because they require only phase II metabolism and are inactivated by direct conjugation in the liver, mechanisms minimally impacted by aging.²⁷

Buspirone. Investigations of anxious older adults have suggested that buspirone is effective for addressing anxiety symptoms.^28,29 Our experience, however, indicates that response to buspirone is inconsistent.

Recommendations. Based on this evidence and our clinical practice, we recommend using SSRIs or SNRIs as first-line treatment for most anxiety disorders in older adults (Table 3).

To minimize nonadherence associated with antidepressants’ delayed onset of action and initial transient “jitters”:

• provide patient education about medication onset and side effects
  
• add a short half-life benzodiazepine for the first few weeks of treatment only
  
• start with small doses and increase gradually.
  

Table 2

Recommended dosages for treating anxiety in older adults

Medication	Starting dosage	Maximum dosage
Selective serotonin reuptake inhibitors
Citalopram	10 mg/d	30 mg/d
Escitalopram	5 mg/d	10 mg/d
Fluvoxamine	25 mg/d	100 mg/d
Paroxetine	10 mg/d	20 mg/d
Sertraline	12.5 mg/d	50 mg/d
Serotonin/norepinephrine reuptake inhibitors
Duloxetine	30 mg/d	60 mg/d
Venlafaxine	37.5 mg/d	150 mg/d
Benzodiazepines
Lorazepam	0.5 mg/d divided bid	1 to 3 mg/d, divided bid or tid
Oxazepam	30 mg/d divided tid	45 to 60 mg/d divided tid or qid
Azapirone
Buspirone	10 to 15 mg/d, divided bid or tid	30 to 60 mg/d divided bid or tid

Table 3

Anxiety in older adults: Recommended interventions

Disorder	First-line treatment(s)	Second-line treatment(s)
Generalized anxiety disorder	SSRIs, SNRIs, buspirone, and/or CBT	Other newer antidepressants*
Panic disorder, with or without agoraphobia	SSRIs, SNRIs, and/or CBT	Other newer antidepressants*
Mixed anxiety and depression	SSRIs or SNRIs	Buspirone, CBT
Anxiety and medical disorders	Identify and treat medical cause, use SSRIs or SNRIs for primary anxiety disorder	Benzodiazepines
* Novel agents such as mirtazapine
CBT: cognitive-behavioral therapy; SNRIs: serotonin/norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors

Psychotherapy as an alternative or adjunct

Researchers have compared the efficacy of CBT—which is effective for depression in older adults³⁰—with that of other psychotherapies for mixed and specific anxiety disorders, including GAD and PD.

For GAD. Multicomponent CBT for GAD typically includes:

• psychoeducation
  
• thought monitoring
  
• cognitive restructuring
  
• progressive muscle relaxation and similar techniques
  
• breathing retraining
  
• problem solving
  
• exposure (imaginal, in vivo, worry)
  
• time management
  
• problem solving.
  

CBT treatment helps older adults with GAD improve on short-term measures of anxiety, worry, depression, and fear. In a clinical trial of 85 older patients with GAD who participated in 15 weekly CBT group sessions, Stanley et al³¹ rated 45% of CBT group patients as responders, compared with 8% of a control group that received minimal contact. Additionally, 55% of CBT participants met DSM-IV-TR diagnostic criteria for GAD, compared with 81% of control patients. CBT group patients maintained improvements across measures of worry, anxiety, depression, fears, and quality of life at 3-, 6-, and 12-month assessments.

 

Six months of group CBT or nondirective supportive psychotherapy have shown similar efficacy in reducing worry, anxiety, and depression scores in older adults with GAD.³² In a randomized trial,³³ group CBT produced slightly greater improvements in anxiety, depression, and pathologic worry among 75 older adults with GAD, compared with a worry discussion group (DG). CBT’s only statistically significant advantage, however, was that patients spent less time worrying immediately after treatment, compared with DG patients. This difference disappeared at 6 months.

For PD. Evidence supports using CBT for older adults with PD. CBT for PD typically includes interventions used for GAD but also integrates interoceptive exposure and tailored psychoeducation regarding panic symptom onset and maintenance. Older adults with PD who received 10 sessions of CBT over 12 weeks improved significantly on all symptoms measured—cognitive, behavioral, physiologic, and depression—in a study by Swales et al.³⁴ These improvements were seen immediately after treatment and at 3-month follow-up. In a separate study, a sample of 43 older adults—most of whom were diagnosed with PD—were randomly assigned to receive CBT or individual, in-home supportive therapy.³⁵ The CBT group reported greater reductions in anxiety and depression.

For mixed anxiety disorders. Several investigations have assessed the efficacy of CBT for older adults with mixed anxiety diagnoses and symptoms.

In one randomized trial, 84 older adults with a principal anxiety disorder diagnosis—GAD, PD, agoraphobia, or social phobia—were assigned to CBT, sertraline (maximum dosage 150 mg/d), or a wait-list.¹⁷ Compared with patients assigned to the waitlist, those in the CBT and sertraline groups improved on measures of anxiety and worry immediately after treatment and at 3-month follow-up. Patients receiving sertraline worried slightly less than those who received CBT. The sertraline and CBT groups did not differ in percentage of subjects who responded to treatment or end-state functioning.

For withdrawal support. Gorenstein et al³⁶ assessed withdrawal from anxiolytic medications among 42 patients age >60 with GAD, PD, comorbid GAD and PD, or anxiety disorder, not otherwise specified. Patients were randomly assigned to CBT plus medical management for medication taper or to medical management alone. Because of a high attrition rate, researchers used data only from subjects who completed the study. Compared with patients receiving medical management only, those who underwent CBT plus medical management had greater declines in anxiety and depressive symptoms from baseline. Many treatment gains were maintained at 6-month follow-up.

CASE CONTINUED: Combination pharmacotherapy CBT

You explain to Ms. W that depressed and anxious older adults frequently perceive memory difficulties. You further relate that it is possible that anxious older adults may experience memory changes because of medication side effects (particularly benzodiazepines) or interference of cognitive functioning by negative mood states. You prescribe sertraline, which is titrated to and maintained at 50 mg/d. Ms. W also participates in 10 psychotherapy sessions, which focus on psychoeducation about symptoms of GAD, relaxation strategies, sleep hygiene, grieving, and cognitive restructuring regarding her worries.

Modifying CBT for older adults. The quality of older adults’ cognitive functioning may affect their response to CBT,³⁷ particularly if they exhibit impaired executive functioning.³⁸ Modifying CBT to meet the needs of older adults has not been systematically investigated.

Mohlman et al³⁹ evaluated the use of modified CBT in 8 older adults with GAD who were randomly assigned to enhanced individual CBT or a waiting list. Strategies used to enhance adherence with cognitive-behavioral procedures included:

• weekly readings of psychoeducational materials that emphasized the relationship between cognitions, behaviors, physiological functioning, and emotions
  
• graphing symptom changes
  
• reminder/troubleshooting phone calls.
  

Using these strategies was associated with lower anxiety and worry symptoms as well as fewer symptoms of GAD or comorbid disorders. The enhanced CBT resulted in improvement on more measures and produced large effect sizes than standard CBT when each intervention was compared with a control group assigned to a waiting list.

CASE CONTINUED: Follow-up evaluation

You refer Ms. W to her primary care physician for follow-up. After 12 weeks of treatment, she reports declining anxiety symptoms. A repeat BAI indicates mild anxiousness, which she describes as minimally affecting her day-to-day activities. She continues sertraline and participation in individual psychotherapy with a particular focus on recent losses in her life.

 

Delivering CBT in primary care. Integrating CBT into anxious older patients’ primary care may be desirable because:

• Older adults prefer to receive psychiatric care in this setting.⁴⁰
  
• Collaborative-care models for depressed and anxious older adults have been successful.⁴¹
  

In collaborative-care models, psychiatrists may supervise a specialized case manager who may identify patients with depression and provide assessment findings and antidepressant treatment support to the patient’s primary care physician. The specialized case manager also may provide psychoeducational information, support, and limited psychotherapy to patients.

A small pilot study that provided CBT in a primary care setting for older adults who met DSM-IV-TR criteria for GAD found statistically and clinically significant declines in self-reported worry, depression, and GAD symptom severity compared with patients receiving care as usual.⁴²

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Lauderdale SA, Kelly K, Sheikh JI. Anxious older adults: prevalence, assessment, and treatment. In: Anthony ME, Maletta GJ, eds. Principles and practice of geriatric psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:429-48.
  

Drug brand names

• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Lorazepam • Ativan
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Disclosure

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

Ms. W, a 73-year-old widow with no psychiatric history, visits her primary care physician because she is concerned about her memory. She denies impairment in other cognitive domains—such as executive function—or activities of daily living.

Ms. W relates prominent worries about her health and finances and those of her grandchildren. She describes daily restlessness, sleep-onset insomnia, difficulty concentrating, and mild episodic dysphoria. She says she’s always been a “worry wart” but her worry and other symptoms have become increasingly intrusive over the past 5 years with a series of deaths in her family. Ms. W’s medical history includes hypertension and type 2 diabetes. Unsure how to treat her, the physician refers Ms. W to a psychiatrist.

Older adults with anxiety symptoms often are dissatisfied with treatment because they believe they receive insufficient help. This complaint is probably valid because limited data support pharmacologic interventions for anxiety in older adults, and therapy is often based on inferences from studies in younger subjects. Moreover, many anxious older patients are treated with benzodiazepines, which increases their risk for cognitive impairment and injuries.^1,2

Fortunately, growing evidence points to 2 treatment modalities for anxiety disorders in patients age ≥65:

• pharmacotherapy with antidepressants, benzodiazepines, and (perhaps) buspirone
  
• cognitive-behavioral therapy (CBT) for generalized anxiety disorder (GAD), panic disorder (PD), and mixed anxiety syndromes.
  

A common, debilitating problem

Anxious older adults report diminished perceived health, physical activities, and quality of life and increased loneliness compared with their nonanxious counterparts.¹ The prevalence of anxiety disorders in older patients ranges from 0.4% for obsessive-compulsive disorder to 11.5% for GAD.³

Older adults with GAD present with a constellation of medical, psychiatric, psychological, and psychosocial features (Table 1).^1,3-12 Anxiety disorders in older adults also may co-occur with major depressive disorder, other psychiatric conditions, or dementia, which can complicate diagnosis and treatment.

Table 1

Is it GAD? Common features in older adults

Demographics
More prevalent at age
More common in women
Medical
Frequent visits to primary care
Low satisfaction with medical care
≥2 chronic physical illnesses
≥1 adaptive behavior limitations
Cognitive impairment, particularly verbal memory
Psychiatric
History of GAD symptoms (5 to ≥20 years)
Physiologic anxiety symptoms: restlessness, fatigue, muscle tension
Depressive symptoms
Prescribed a benzodiazepine
Presence of anxiety disorders
Suicidal ideation, particularly if depressed
Psychological
External locus of control
Neuroticism
Psychosocial
Limited social network
Perceived low instrumental support
Recent losses and traumatic life events
Loss of partner
GAD: generalized anxiety disorder
Source: References 1,3-12

CASE CONTINUED: Anxious, not depressed

You screen Ms. W with the Geriatric Depression Scale (short form; GDS) and Beck Anxiety Inventory (BAI). Her scores indicate no depression and moderate anxiousness. A neuropsychological screen finds no cognitive impairments. Based on the clinical interview and screening, Ms. W meets DSM-IV-TR criteria for GAD.

Psychopharmacologic interventions are first-line treatment for older adults with anxiety disorders, but you might consider other strategies because:

• Older patients may have increased vulnerability to medication side effects.
  
• Few randomized, placebo-controlled trials have examined psychopharmacologic interventions specifically for anxious older adults.
  

Evidence supports using psychotherapy as an alternative or adjunct to pharmacotherapy for treating anxiety symptoms. A meta-analysis of 15 studies that included 495 adults (mean age 69.5 years) with late-life anxiety symptoms and 20 psychotherapeutic interventions indicated that psychotherapy was reliably more effective than no treatment.¹³

First-line pharmacotherapies

When selecting pharmacotherapy for an older adult with anxiety, take into account:

• physiologic changes in drug metabolism (older patients metabolize drugs more slowly than younger patients)
  
• comorbid medical problems
  
• polypharmacy (many older patients are taking multiple medications for multiple conditions, which increases the risk of drug-drug interactions).
  

Also consider prior treatment response and symptom severity when choosing the medication you feel will be most tolerable. “Start low and go slow” to avoid side effects while titrating the medication to the optimal dosage (Table 2).

Pharmacologic management of anxiety typically has included benzodiazepines, tricyclic antidepressants, barbiturates, and antihistamines. Newer antidepressants have emerged as first-line treatment for several anxiety disorders and mixed anxiety-depression syndromes, however, because of their more tolerable side-effect profiles, especially when used long-term.¹⁴ These antidepressants include:

• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin/norepinephrine reuptake inhibitors (SNRIs).
  

SSRIs are useful for treating anxiety disorders in young and middle-aged adults, as shown in randomized, placebo-controlled clinical trials. Much less evidence exists, however, on the use of SSRIs in anxious older adults.

Citalopram—started at 10 mg/d and titrated to 30 mg/d as tolerated—was used in the only prospective, double-blind, randomized, controlled trial of an SSRI in older patients with anxiety disorders. In this 8-week trial, Clinical Global Impression scale scores and Hamilton Anxiety scale scores improved.¹⁵ In other investigations:

 

• Paroxetine, averaging approximately 28 mg/d, produced a similar response in older and younger adults with PD in terms of efficacy and tolerability in a naturalistic follow-up trial.¹⁶
  
• Sertraline, started at 25 mg/d and titrated to 100 mg/d (maximum 150 mg/d), when combined with CBT was effective for treating older adults with anxiety disorders in a randomized, placebo-controlled trial¹⁷ and specifically for those with PD in an open-label trial.¹⁸
  
• Fluvoxamine, median 200 mg/d, reduced anxiety symptoms in an open-label study of 12 older adults with various anxiety disorders. Most patients with GAD (57%) responded to fluvoxamine, but 3 patients with PD did not.¹⁹
  
• We found no studies of fluoxetine for anxiety symptoms in older adults.
  

An important caveat to these findings is data suggesting older adults with mixed anxiety and depression (MAD) may take longer to respond to pharmacologic and psychotherapeutic interventions than older adults with anxiety or depression alone.^20,21 On the other hand, Lenze et al²² found no evidence of a lower or slower response to paroxetine in depressed older adults with or without anxiety. In an open-label, flexible-dose study, escitalopram, 10 to 20 mg/ d, reduced comorbid anxiety and depression symptoms and improved social functioning in 17 older outpatients.²³

SNRIs. In a retrospective, pooled analysis of 5 randomized, placebo-controlled trials²⁴ venlafaxine ER, 37.5 to 225 mg/d, was significantly more effective than placebo in treating older adults with GAD. Several studies suggest duloxetine may be effective for treating GAD in adults, but none examined efficacy specifically for older adults.

Benzodiazepines’ primary benefits are rapid onset and minimal cardiovascular effects. They remain the mainstay of pharmacologic therapy for acute anxiety and can be useful as initial, short-term adjunctive therapy with SSRIs and SNRIs.

Using benzodiazepines for more than a few weeks in older adults is not recommended, however.¹⁴ Potential complications of long-term benzodiazepine use in these patients include:

• excessive daytime drowsiness
  
• cognitive and psychomotor impairment
  
• confusion
  
• risk of falls
  
• depression
  
• paradoxical reactions
  
• amnesic syndromes
  
• respiratory problems
  
• potential for abuse/dependence
  
• breakthrough withdrawal reactions.^2,25,26
  

For older patients, short half-life benzodiazepines—such as lorazepam (maximum 1 to 3 mg/d divided bid or tid) or oxazepam (maximum 45 to 60 mg/d divided tid or qid)—are preferred because they require only phase II metabolism and are inactivated by direct conjugation in the liver, mechanisms minimally impacted by aging.²⁷

Buspirone. Investigations of anxious older adults have suggested that buspirone is effective for addressing anxiety symptoms.^28,29 Our experience, however, indicates that response to buspirone is inconsistent.

Recommendations. Based on this evidence and our clinical practice, we recommend using SSRIs or SNRIs as first-line treatment for most anxiety disorders in older adults (Table 3).

To minimize nonadherence associated with antidepressants’ delayed onset of action and initial transient “jitters”:

• provide patient education about medication onset and side effects
  
• add a short half-life benzodiazepine for the first few weeks of treatment only
  
• start with small doses and increase gradually.
  

Table 2

Recommended dosages for treating anxiety in older adults

Medication	Starting dosage	Maximum dosage
Selective serotonin reuptake inhibitors
Citalopram	10 mg/d	30 mg/d
Escitalopram	5 mg/d	10 mg/d
Fluvoxamine	25 mg/d	100 mg/d
Paroxetine	10 mg/d	20 mg/d
Sertraline	12.5 mg/d	50 mg/d
Serotonin/norepinephrine reuptake inhibitors
Duloxetine	30 mg/d	60 mg/d
Venlafaxine	37.5 mg/d	150 mg/d
Benzodiazepines
Lorazepam	0.5 mg/d divided bid	1 to 3 mg/d, divided bid or tid
Oxazepam	30 mg/d divided tid	45 to 60 mg/d divided tid or qid
Azapirone
Buspirone	10 to 15 mg/d, divided bid or tid	30 to 60 mg/d divided bid or tid

Table 3

Anxiety in older adults: Recommended interventions

Disorder	First-line treatment(s)	Second-line treatment(s)
Generalized anxiety disorder	SSRIs, SNRIs, buspirone, and/or CBT	Other newer antidepressants*
Panic disorder, with or without agoraphobia	SSRIs, SNRIs, and/or CBT	Other newer antidepressants*
Mixed anxiety and depression	SSRIs or SNRIs	Buspirone, CBT
Anxiety and medical disorders	Identify and treat medical cause, use SSRIs or SNRIs for primary anxiety disorder	Benzodiazepines
* Novel agents such as mirtazapine
CBT: cognitive-behavioral therapy; SNRIs: serotonin/norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors

Psychotherapy as an alternative or adjunct

Researchers have compared the efficacy of CBT—which is effective for depression in older adults³⁰—with that of other psychotherapies for mixed and specific anxiety disorders, including GAD and PD.

For GAD. Multicomponent CBT for GAD typically includes:

• psychoeducation
  
• thought monitoring
  
• cognitive restructuring
  
• progressive muscle relaxation and similar techniques
  
• breathing retraining
  
• problem solving
  
• exposure (imaginal, in vivo, worry)
  
• time management
  
• problem solving.
  

CBT treatment helps older adults with GAD improve on short-term measures of anxiety, worry, depression, and fear. In a clinical trial of 85 older patients with GAD who participated in 15 weekly CBT group sessions, Stanley et al³¹ rated 45% of CBT group patients as responders, compared with 8% of a control group that received minimal contact. Additionally, 55% of CBT participants met DSM-IV-TR diagnostic criteria for GAD, compared with 81% of control patients. CBT group patients maintained improvements across measures of worry, anxiety, depression, fears, and quality of life at 3-, 6-, and 12-month assessments.

 

Six months of group CBT or nondirective supportive psychotherapy have shown similar efficacy in reducing worry, anxiety, and depression scores in older adults with GAD.³² In a randomized trial,³³ group CBT produced slightly greater improvements in anxiety, depression, and pathologic worry among 75 older adults with GAD, compared with a worry discussion group (DG). CBT’s only statistically significant advantage, however, was that patients spent less time worrying immediately after treatment, compared with DG patients. This difference disappeared at 6 months.

For PD. Evidence supports using CBT for older adults with PD. CBT for PD typically includes interventions used for GAD but also integrates interoceptive exposure and tailored psychoeducation regarding panic symptom onset and maintenance. Older adults with PD who received 10 sessions of CBT over 12 weeks improved significantly on all symptoms measured—cognitive, behavioral, physiologic, and depression—in a study by Swales et al.³⁴ These improvements were seen immediately after treatment and at 3-month follow-up. In a separate study, a sample of 43 older adults—most of whom were diagnosed with PD—were randomly assigned to receive CBT or individual, in-home supportive therapy.³⁵ The CBT group reported greater reductions in anxiety and depression.

For mixed anxiety disorders. Several investigations have assessed the efficacy of CBT for older adults with mixed anxiety diagnoses and symptoms.

In one randomized trial, 84 older adults with a principal anxiety disorder diagnosis—GAD, PD, agoraphobia, or social phobia—were assigned to CBT, sertraline (maximum dosage 150 mg/d), or a wait-list.¹⁷ Compared with patients assigned to the waitlist, those in the CBT and sertraline groups improved on measures of anxiety and worry immediately after treatment and at 3-month follow-up. Patients receiving sertraline worried slightly less than those who received CBT. The sertraline and CBT groups did not differ in percentage of subjects who responded to treatment or end-state functioning.

For withdrawal support. Gorenstein et al³⁶ assessed withdrawal from anxiolytic medications among 42 patients age >60 with GAD, PD, comorbid GAD and PD, or anxiety disorder, not otherwise specified. Patients were randomly assigned to CBT plus medical management for medication taper or to medical management alone. Because of a high attrition rate, researchers used data only from subjects who completed the study. Compared with patients receiving medical management only, those who underwent CBT plus medical management had greater declines in anxiety and depressive symptoms from baseline. Many treatment gains were maintained at 6-month follow-up.

CASE CONTINUED: Combination pharmacotherapy CBT

You explain to Ms. W that depressed and anxious older adults frequently perceive memory difficulties. You further relate that it is possible that anxious older adults may experience memory changes because of medication side effects (particularly benzodiazepines) or interference of cognitive functioning by negative mood states. You prescribe sertraline, which is titrated to and maintained at 50 mg/d. Ms. W also participates in 10 psychotherapy sessions, which focus on psychoeducation about symptoms of GAD, relaxation strategies, sleep hygiene, grieving, and cognitive restructuring regarding her worries.

Modifying CBT for older adults. The quality of older adults’ cognitive functioning may affect their response to CBT,³⁷ particularly if they exhibit impaired executive functioning.³⁸ Modifying CBT to meet the needs of older adults has not been systematically investigated.

Mohlman et al³⁹ evaluated the use of modified CBT in 8 older adults with GAD who were randomly assigned to enhanced individual CBT or a waiting list. Strategies used to enhance adherence with cognitive-behavioral procedures included:

• weekly readings of psychoeducational materials that emphasized the relationship between cognitions, behaviors, physiological functioning, and emotions
  
• graphing symptom changes
  
• reminder/troubleshooting phone calls.
  

Using these strategies was associated with lower anxiety and worry symptoms as well as fewer symptoms of GAD or comorbid disorders. The enhanced CBT resulted in improvement on more measures and produced large effect sizes than standard CBT when each intervention was compared with a control group assigned to a waiting list.

CASE CONTINUED: Follow-up evaluation

You refer Ms. W to her primary care physician for follow-up. After 12 weeks of treatment, she reports declining anxiety symptoms. A repeat BAI indicates mild anxiousness, which she describes as minimally affecting her day-to-day activities. She continues sertraline and participation in individual psychotherapy with a particular focus on recent losses in her life.

 

Delivering CBT in primary care. Integrating CBT into anxious older patients’ primary care may be desirable because:

• Older adults prefer to receive psychiatric care in this setting.⁴⁰
  
• Collaborative-care models for depressed and anxious older adults have been successful.⁴¹
  

In collaborative-care models, psychiatrists may supervise a specialized case manager who may identify patients with depression and provide assessment findings and antidepressant treatment support to the patient’s primary care physician. The specialized case manager also may provide psychoeducational information, support, and limited psychotherapy to patients.

A small pilot study that provided CBT in a primary care setting for older adults who met DSM-IV-TR criteria for GAD found statistically and clinically significant declines in self-reported worry, depression, and GAD symptom severity compared with patients receiving care as usual.⁴²

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Lauderdale SA, Kelly K, Sheikh JI. Anxious older adults: prevalence, assessment, and treatment. In: Anthony ME, Maletta GJ, eds. Principles and practice of geriatric psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:429-48.
  

Drug brand names

• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Lorazepam • Ativan
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Disclosure

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

Ms. W, a 73-year-old widow with no psychiatric history, visits her primary care physician because she is concerned about her memory. She denies impairment in other cognitive domains—such as executive function—or activities of daily living.

Ms. W relates prominent worries about her health and finances and those of her grandchildren. She describes daily restlessness, sleep-onset insomnia, difficulty concentrating, and mild episodic dysphoria. She says she’s always been a “worry wart” but her worry and other symptoms have become increasingly intrusive over the past 5 years with a series of deaths in her family. Ms. W’s medical history includes hypertension and type 2 diabetes. Unsure how to treat her, the physician refers Ms. W to a psychiatrist.

Older adults with anxiety symptoms often are dissatisfied with treatment because they believe they receive insufficient help. This complaint is probably valid because limited data support pharmacologic interventions for anxiety in older adults, and therapy is often based on inferences from studies in younger subjects. Moreover, many anxious older patients are treated with benzodiazepines, which increases their risk for cognitive impairment and injuries.^1,2

Fortunately, growing evidence points to 2 treatment modalities for anxiety disorders in patients age ≥65:

• pharmacotherapy with antidepressants, benzodiazepines, and (perhaps) buspirone
  
• cognitive-behavioral therapy (CBT) for generalized anxiety disorder (GAD), panic disorder (PD), and mixed anxiety syndromes.
  

A common, debilitating problem

Anxious older adults report diminished perceived health, physical activities, and quality of life and increased loneliness compared with their nonanxious counterparts.¹ The prevalence of anxiety disorders in older patients ranges from 0.4% for obsessive-compulsive disorder to 11.5% for GAD.³

Older adults with GAD present with a constellation of medical, psychiatric, psychological, and psychosocial features (Table 1).^1,3-12 Anxiety disorders in older adults also may co-occur with major depressive disorder, other psychiatric conditions, or dementia, which can complicate diagnosis and treatment.

Table 1

Is it GAD? Common features in older adults

Demographics
More prevalent at age
More common in women
Medical
Frequent visits to primary care
Low satisfaction with medical care
≥2 chronic physical illnesses
≥1 adaptive behavior limitations
Cognitive impairment, particularly verbal memory
Psychiatric
History of GAD symptoms (5 to ≥20 years)
Physiologic anxiety symptoms: restlessness, fatigue, muscle tension
Depressive symptoms
Prescribed a benzodiazepine
Presence of anxiety disorders
Suicidal ideation, particularly if depressed
Psychological
External locus of control
Neuroticism
Psychosocial
Limited social network
Perceived low instrumental support
Recent losses and traumatic life events
Loss of partner
GAD: generalized anxiety disorder
Source: References 1,3-12

CASE CONTINUED: Anxious, not depressed

You screen Ms. W with the Geriatric Depression Scale (short form; GDS) and Beck Anxiety Inventory (BAI). Her scores indicate no depression and moderate anxiousness. A neuropsychological screen finds no cognitive impairments. Based on the clinical interview and screening, Ms. W meets DSM-IV-TR criteria for GAD.

Psychopharmacologic interventions are first-line treatment for older adults with anxiety disorders, but you might consider other strategies because:

• Older patients may have increased vulnerability to medication side effects.
  
• Few randomized, placebo-controlled trials have examined psychopharmacologic interventions specifically for anxious older adults.
  

Evidence supports using psychotherapy as an alternative or adjunct to pharmacotherapy for treating anxiety symptoms. A meta-analysis of 15 studies that included 495 adults (mean age 69.5 years) with late-life anxiety symptoms and 20 psychotherapeutic interventions indicated that psychotherapy was reliably more effective than no treatment.¹³

First-line pharmacotherapies

When selecting pharmacotherapy for an older adult with anxiety, take into account:

• physiologic changes in drug metabolism (older patients metabolize drugs more slowly than younger patients)
  
• comorbid medical problems
  
• polypharmacy (many older patients are taking multiple medications for multiple conditions, which increases the risk of drug-drug interactions).
  

Also consider prior treatment response and symptom severity when choosing the medication you feel will be most tolerable. “Start low and go slow” to avoid side effects while titrating the medication to the optimal dosage (Table 2).

Pharmacologic management of anxiety typically has included benzodiazepines, tricyclic antidepressants, barbiturates, and antihistamines. Newer antidepressants have emerged as first-line treatment for several anxiety disorders and mixed anxiety-depression syndromes, however, because of their more tolerable side-effect profiles, especially when used long-term.¹⁴ These antidepressants include:

• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin/norepinephrine reuptake inhibitors (SNRIs).
  

SSRIs are useful for treating anxiety disorders in young and middle-aged adults, as shown in randomized, placebo-controlled clinical trials. Much less evidence exists, however, on the use of SSRIs in anxious older adults.

Citalopram—started at 10 mg/d and titrated to 30 mg/d as tolerated—was used in the only prospective, double-blind, randomized, controlled trial of an SSRI in older patients with anxiety disorders. In this 8-week trial, Clinical Global Impression scale scores and Hamilton Anxiety scale scores improved.¹⁵ In other investigations:

 

• Paroxetine, averaging approximately 28 mg/d, produced a similar response in older and younger adults with PD in terms of efficacy and tolerability in a naturalistic follow-up trial.¹⁶
  
• Sertraline, started at 25 mg/d and titrated to 100 mg/d (maximum 150 mg/d), when combined with CBT was effective for treating older adults with anxiety disorders in a randomized, placebo-controlled trial¹⁷ and specifically for those with PD in an open-label trial.¹⁸
  
• Fluvoxamine, median 200 mg/d, reduced anxiety symptoms in an open-label study of 12 older adults with various anxiety disorders. Most patients with GAD (57%) responded to fluvoxamine, but 3 patients with PD did not.¹⁹
  
• We found no studies of fluoxetine for anxiety symptoms in older adults.
  

An important caveat to these findings is data suggesting older adults with mixed anxiety and depression (MAD) may take longer to respond to pharmacologic and psychotherapeutic interventions than older adults with anxiety or depression alone.^20,21 On the other hand, Lenze et al²² found no evidence of a lower or slower response to paroxetine in depressed older adults with or without anxiety. In an open-label, flexible-dose study, escitalopram, 10 to 20 mg/ d, reduced comorbid anxiety and depression symptoms and improved social functioning in 17 older outpatients.²³

SNRIs. In a retrospective, pooled analysis of 5 randomized, placebo-controlled trials²⁴ venlafaxine ER, 37.5 to 225 mg/d, was significantly more effective than placebo in treating older adults with GAD. Several studies suggest duloxetine may be effective for treating GAD in adults, but none examined efficacy specifically for older adults.

Benzodiazepines’ primary benefits are rapid onset and minimal cardiovascular effects. They remain the mainstay of pharmacologic therapy for acute anxiety and can be useful as initial, short-term adjunctive therapy with SSRIs and SNRIs.

Using benzodiazepines for more than a few weeks in older adults is not recommended, however.¹⁴ Potential complications of long-term benzodiazepine use in these patients include:

• excessive daytime drowsiness
  
• cognitive and psychomotor impairment
  
• confusion
  
• risk of falls
  
• depression
  
• paradoxical reactions
  
• amnesic syndromes
  
• respiratory problems
  
• potential for abuse/dependence
  
• breakthrough withdrawal reactions.^2,25,26
  

For older patients, short half-life benzodiazepines—such as lorazepam (maximum 1 to 3 mg/d divided bid or tid) or oxazepam (maximum 45 to 60 mg/d divided tid or qid)—are preferred because they require only phase II metabolism and are inactivated by direct conjugation in the liver, mechanisms minimally impacted by aging.²⁷

Buspirone. Investigations of anxious older adults have suggested that buspirone is effective for addressing anxiety symptoms.^28,29 Our experience, however, indicates that response to buspirone is inconsistent.

Recommendations. Based on this evidence and our clinical practice, we recommend using SSRIs or SNRIs as first-line treatment for most anxiety disorders in older adults (Table 3).

To minimize nonadherence associated with antidepressants’ delayed onset of action and initial transient “jitters”:

• provide patient education about medication onset and side effects
  
• add a short half-life benzodiazepine for the first few weeks of treatment only
  
• start with small doses and increase gradually.
  

Table 2

Recommended dosages for treating anxiety in older adults

Medication	Starting dosage	Maximum dosage
Selective serotonin reuptake inhibitors
Citalopram	10 mg/d	30 mg/d
Escitalopram	5 mg/d	10 mg/d
Fluvoxamine	25 mg/d	100 mg/d
Paroxetine	10 mg/d	20 mg/d
Sertraline	12.5 mg/d	50 mg/d
Serotonin/norepinephrine reuptake inhibitors
Duloxetine	30 mg/d	60 mg/d
Venlafaxine	37.5 mg/d	150 mg/d
Benzodiazepines
Lorazepam	0.5 mg/d divided bid	1 to 3 mg/d, divided bid or tid
Oxazepam	30 mg/d divided tid	45 to 60 mg/d divided tid or qid
Azapirone
Buspirone	10 to 15 mg/d, divided bid or tid	30 to 60 mg/d divided bid or tid

Table 3

Anxiety in older adults: Recommended interventions

Disorder	First-line treatment(s)	Second-line treatment(s)
Generalized anxiety disorder	SSRIs, SNRIs, buspirone, and/or CBT	Other newer antidepressants*
Panic disorder, with or without agoraphobia	SSRIs, SNRIs, and/or CBT	Other newer antidepressants*
Mixed anxiety and depression	SSRIs or SNRIs	Buspirone, CBT
Anxiety and medical disorders	Identify and treat medical cause, use SSRIs or SNRIs for primary anxiety disorder	Benzodiazepines
* Novel agents such as mirtazapine
CBT: cognitive-behavioral therapy; SNRIs: serotonin/norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors

Psychotherapy as an alternative or adjunct

Researchers have compared the efficacy of CBT—which is effective for depression in older adults³⁰—with that of other psychotherapies for mixed and specific anxiety disorders, including GAD and PD.

For GAD. Multicomponent CBT for GAD typically includes:

• psychoeducation
  
• thought monitoring
  
• cognitive restructuring
  
• progressive muscle relaxation and similar techniques
  
• breathing retraining
  
• problem solving
  
• exposure (imaginal, in vivo, worry)
  
• time management
  
• problem solving.
  

CBT treatment helps older adults with GAD improve on short-term measures of anxiety, worry, depression, and fear. In a clinical trial of 85 older patients with GAD who participated in 15 weekly CBT group sessions, Stanley et al³¹ rated 45% of CBT group patients as responders, compared with 8% of a control group that received minimal contact. Additionally, 55% of CBT participants met DSM-IV-TR diagnostic criteria for GAD, compared with 81% of control patients. CBT group patients maintained improvements across measures of worry, anxiety, depression, fears, and quality of life at 3-, 6-, and 12-month assessments.

 

Six months of group CBT or nondirective supportive psychotherapy have shown similar efficacy in reducing worry, anxiety, and depression scores in older adults with GAD.³² In a randomized trial,³³ group CBT produced slightly greater improvements in anxiety, depression, and pathologic worry among 75 older adults with GAD, compared with a worry discussion group (DG). CBT’s only statistically significant advantage, however, was that patients spent less time worrying immediately after treatment, compared with DG patients. This difference disappeared at 6 months.

For PD. Evidence supports using CBT for older adults with PD. CBT for PD typically includes interventions used for GAD but also integrates interoceptive exposure and tailored psychoeducation regarding panic symptom onset and maintenance. Older adults with PD who received 10 sessions of CBT over 12 weeks improved significantly on all symptoms measured—cognitive, behavioral, physiologic, and depression—in a study by Swales et al.³⁴ These improvements were seen immediately after treatment and at 3-month follow-up. In a separate study, a sample of 43 older adults—most of whom were diagnosed with PD—were randomly assigned to receive CBT or individual, in-home supportive therapy.³⁵ The CBT group reported greater reductions in anxiety and depression.

For mixed anxiety disorders. Several investigations have assessed the efficacy of CBT for older adults with mixed anxiety diagnoses and symptoms.

In one randomized trial, 84 older adults with a principal anxiety disorder diagnosis—GAD, PD, agoraphobia, or social phobia—were assigned to CBT, sertraline (maximum dosage 150 mg/d), or a wait-list.¹⁷ Compared with patients assigned to the waitlist, those in the CBT and sertraline groups improved on measures of anxiety and worry immediately after treatment and at 3-month follow-up. Patients receiving sertraline worried slightly less than those who received CBT. The sertraline and CBT groups did not differ in percentage of subjects who responded to treatment or end-state functioning.

For withdrawal support. Gorenstein et al³⁶ assessed withdrawal from anxiolytic medications among 42 patients age >60 with GAD, PD, comorbid GAD and PD, or anxiety disorder, not otherwise specified. Patients were randomly assigned to CBT plus medical management for medication taper or to medical management alone. Because of a high attrition rate, researchers used data only from subjects who completed the study. Compared with patients receiving medical management only, those who underwent CBT plus medical management had greater declines in anxiety and depressive symptoms from baseline. Many treatment gains were maintained at 6-month follow-up.

CASE CONTINUED: Combination pharmacotherapy CBT

You explain to Ms. W that depressed and anxious older adults frequently perceive memory difficulties. You further relate that it is possible that anxious older adults may experience memory changes because of medication side effects (particularly benzodiazepines) or interference of cognitive functioning by negative mood states. You prescribe sertraline, which is titrated to and maintained at 50 mg/d. Ms. W also participates in 10 psychotherapy sessions, which focus on psychoeducation about symptoms of GAD, relaxation strategies, sleep hygiene, grieving, and cognitive restructuring regarding her worries.

Modifying CBT for older adults. The quality of older adults’ cognitive functioning may affect their response to CBT,³⁷ particularly if they exhibit impaired executive functioning.³⁸ Modifying CBT to meet the needs of older adults has not been systematically investigated.

Mohlman et al³⁹ evaluated the use of modified CBT in 8 older adults with GAD who were randomly assigned to enhanced individual CBT or a waiting list. Strategies used to enhance adherence with cognitive-behavioral procedures included:

• weekly readings of psychoeducational materials that emphasized the relationship between cognitions, behaviors, physiological functioning, and emotions
  
• graphing symptom changes
  
• reminder/troubleshooting phone calls.
  

Using these strategies was associated with lower anxiety and worry symptoms as well as fewer symptoms of GAD or comorbid disorders. The enhanced CBT resulted in improvement on more measures and produced large effect sizes than standard CBT when each intervention was compared with a control group assigned to a waiting list.

CASE CONTINUED: Follow-up evaluation

You refer Ms. W to her primary care physician for follow-up. After 12 weeks of treatment, she reports declining anxiety symptoms. A repeat BAI indicates mild anxiousness, which she describes as minimally affecting her day-to-day activities. She continues sertraline and participation in individual psychotherapy with a particular focus on recent losses in her life.

 

Delivering CBT in primary care. Integrating CBT into anxious older patients’ primary care may be desirable because:

• Older adults prefer to receive psychiatric care in this setting.⁴⁰
  
• Collaborative-care models for depressed and anxious older adults have been successful.⁴¹
  

In collaborative-care models, psychiatrists may supervise a specialized case manager who may identify patients with depression and provide assessment findings and antidepressant treatment support to the patient’s primary care physician. The specialized case manager also may provide psychoeducational information, support, and limited psychotherapy to patients.

A small pilot study that provided CBT in a primary care setting for older adults who met DSM-IV-TR criteria for GAD found statistically and clinically significant declines in self-reported worry, depression, and GAD symptom severity compared with patients receiving care as usual.⁴²

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Lauderdale SA, Kelly K, Sheikh JI. Anxious older adults: prevalence, assessment, and treatment. In: Anthony ME, Maletta GJ, eds. Principles and practice of geriatric psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:429-48.
  

Drug brand names

• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Lorazepam • Ativan
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Disclosure

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

Children of alcoholics have a 40% to 60% increased risk of developing severe alcohol-related problems¹—a harsh legacy recognized for >30 years. Now, as the result of rapidly growing evidence, we can explain in greater detail why alcoholism runs in families when discussing alcohol dependence with patients.

Individuals vary in response to medications and substances of abuse, and genetic research is revealing the heritable origins. Numerous genetic variations are known to influence response to alcohol, as well as alcoholism’s pathophysiology, clinical manifestations, and treatment. Pieces are still missing from this complex picture, but investigators are identifying possible risk factors for alcoholism and matching potential responders with treatments such as naltrexone and acamprosate.

This article provides a progress report on contemporary genetic research of alcoholism. Our goal is to inform your clinical practice by describing:

• new understandings of the genetics of alcoholism
• how researchers identify relationships between genetic variations and clinical/behavioral phenomena
• practical implications of this knowledge.

Genetic variations and risk of addiction

No single gene appears to cause alcoholism. Many genetic variations that accumulated during evolution likely contribute to individual differences in response to alcohol and susceptibility to developing alcohol-related problems. A growing number of genetic variations have been associated with increased alcohol tolerance, consumption, and other related phenotypes.

Like other addictive substances, alcohol triggers pharmacodynamic effects by interacting with a variety of molecular targets (Figure 1).² These target proteins in turn interact with specific signaling proteins and trigger responses in complex functional pathways. Genetic variations may affect the structure of genes coding for proteins that constitute pathways involved in alcohol’s effects on target proteins (pharmacodynamics) or its metabolism (pharmacokinetics). If such variations alter the production, function, or stability of these proteins, the pathway’s function also may be altered and produce behavioral phenotypes—such as high or low sensitivity to alcohol’s effects.

Alcoholism-related phenotypes. DSM-IV-TR diagnostic criteria include some but not all of the multiple phenotypes within alcoholism’s clinical presentation. Researchers in the Collaborative Studies on Genetics of Alcoholism (COGA)³ identified chromosome regions linked to alcoholism-related phenotypes, including:

• alcohol dependence⁴
• later age of drinking onset and increased harm avoidance⁵
• alcoholism and depression⁶
• alcohol sensitivity⁷
• alcohol consumption.⁸

To identify genes of interest within these chromosome regions, researchers used transitional phenotypes (endophenotypes) that “lie on the pathway between genes and disease,”^9,10 and allowed them to characterize the neural systems affected by gene risk variants.¹¹ As a result, they found associations among variations in the GABRA2 gene, (encoding the alpha-2 subunit of the GABAA receptor), specific brain oscillations (electrophysiologic endophenotype), and predisposition to alcohol dependence.^12,13 By this same strategy, researchers discovered an association between the endophenotype (low-level of response to alcohol) and some genotypes, including at least 1 short allele of the serotonin transporter gene SLC6A4.¹⁴

Figure 1
Known molecular targets for alcohol and other drugs of abuse

Effects of drugs of abuse (black arrows) influence intracellular signaling pathways (blue arrows) to produce immediate and long-term changes in cell function.
cAMP: cyclic adenosine monophosphate; GABAA: gamma-aminobutyric acid A receptor; Gi, Gs, Gq: G proteins (heterotrimeric guanine nucleotide-binding proteins) MAPK: mitogen-activated protein kinase; N-cholino receptor: nicotinic cholinoreceptor; NMDA: N-methyl-D-aspartate; PKA: protein kinase A
Source: Created for CURRENT PSYCHIATRY from information in reference 2

Alcohol metabolism

Alcohol is metabolized to acetic acid through primary and auxiliary pathways involving alcohol and acetaldehyde dehydrogenases (ADH/ALDH) and the microsomal ethanol oxidizing system (cytochrome P-450 [CYP] 2E1)¹⁵ (Figure 2). Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol needed to be metabolized. Catalase and fatty acid ethyl ester synthases play a minor role under normal conditions but may be implicated in alcohol-induced organ damage.¹⁶

ADH/ALDH pathway. From one individual to another, the ability to metabolize ethyl alcohol varies up to 3- to 4-fold.¹⁷ In European and Amerindian samples, a genetic link has been identified between alcoholism and the 4q21-23 region on chromosome 4.¹⁸ This region contains a cluster of 7 genes encoding for alcohol dehydrogenases (ADH), including 3 Class I genes—ADH1A, ADH1B, and ADH1C—coding for the corresponding proteins that play a major role in alcohol metabolism.¹⁹ In eastern Asian samples, alleles encoding high activity enzymes (ADH1B*47His and ADH1C*349Ile) are significantly less frequent in alcoholics compared with nonalcoholic controls.²⁰

Mitochondrial ALDH2 protein plays the central role in acetaldehyde metabolism and is highly expressed in the liver, stomach, and other tissues—including the brain.²¹ The ALDH2*2 gene variant encodes for a catalytically inactive enzyme, thus inhibiting acetaldehyde metabolism and causing a facial flushing reaction.²² The ALDH2*2 allele has a relatively high frequency in Asians but also is found in other populations.²³ Meta-analyses of published data indicate that possessing either of the variant alleles in the ADH1B and ALDH2 genes is protective against alcohol dependence in Asians.²⁴

 

The ADH4 enzyme catalyzes oxidation or reduction of numerous substrates—including long-chain aliphatic alcohols and aromatic aldehydes—and becomes involved in alcohol metabolism at moderate to high concentrations. The -75A allele of the ADH4 gene has promoter activity more than twice that of the -75C allele and significantly affects its expression.²⁵ This substitution in the promoter region, as well as A/G SNP (rs1042364)—a single nucleotide polymorphism (SNP)—at exon 9, has been associated with an increased risk for alcohol and drug dependence in European Americans.²⁶

Finally, variations in the ADH7 gene may play a protective role against alcoholism through epistatic effects.²⁷

The CYP 2E1 pathway has low initial catalytic efficiency compared with the ADH/ALDH pathway, but it may metabolize alcohol up to 10 times faster after chronic alcohol consumption or cigarette smoking and accounts for metabolic tolerance.²⁸ CYP 2E1 is involved in metabolizing both alcohol and acetaldehyde.²⁹ The CYP 2E1*1D polymorphism has been associated with greater inducibility as well as alcohol and nicotine dependence.³⁰

Thus, linkage and association studies support the association of phenotypes related to alcohol response and dependence with variations in genes that code for proteins involved in alcohol’s pharmacodynamic and pharmacokinetic effects. Each of these findings is important, but conceptual models organizing them all and explaining their role in alcohol’s effects and predisposition to alcoholism have yet to be constructed.

Figure 2
Genetic variations that affect alcohol metabolism pathways

Genetic variations affect the efficiency of primary and auxiliary pathways by which ethyl alcohol is metabolized to acetaldehyde and acetic acid. Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol to be metabolized.
ADH: alcohol dehydrogenase; ALDH: acetaldehyde dehydrogenase; P450CYP 2E1: cytochrome P450, family 2, subfamily E, polypeptide 1; A/G SNP: adenine/guanine single nucleotide polymorphism

Phenotype-genotype relationships

Alcohol—unlike most other addictive substances—does not have a specific receptor and is believed to act by disturbing the balance between excitatory and inhibitory neurotransmission in the neural system. Consequently, researchers explore relationships between genetics and alcohol-related problems using 2 approaches:

• Forward genetics (discovering disease-related genes via genome-wide studies and then studying their function; examples include linkage and genome-wide association studies [GWAS]).
• Reverse genetics (testing whether candidate genes and polymorphisms identified in animal studies as relevant for biological effects also exist in humans and are relevant to the phenotype).³¹

When searching for relationships between genotypes and phenotypes, both approaches must take into account a framework of functional anatomic and physiologic connections (Figure 3).

Linkage studies. The goal of linkage studies is to find a link between a phenotypic variation (ideally a measurable trait, such as number of drinks necessary for intoxication) and the chromosomal marker expected to be in the vicinity of the disease-specific gene variation. An advantage of linkage studies is that they can be started without knowing specific DNA sequences. Their limitations include:

• limited power when applied to complex diseases such as alcoholism
• they do not yield gene-specific information
• their success is highly dependent on family members’ willingness to participate.

Association studies. Candidate gene-based association studies are designed to directly test a potential association between the phenotype of interest and a known genomic sequence variation. This approach provides adequate power to study variations with modest effects and allows use of DNA from unrelated individuals. The candidate gene approach has revealed associations between specific genomic variations and phenotypes related to alcohol misuse and alcoholism (Table).

Like linkage studies, association studies have their own challenges and limitations, such as:

• historically high false-positive rates
• confounding risks (allele frequencies may vary because of ethnic stratification rather than disease predisposition).

To address these challenges, researchers must carefully choose behavioral, physiologic, or intermediate phenotypes and genotype variations, as well as control subjects and sample sizes. Replication studies are necessary to rule out false-positive associations. In fact, only some of the findings depicted in the Table—those related to GABRA2 and GABRA6 and few other genes—have been replicated.

Genome-wide association studies are a powerful new method for studying relationships between genomic variability and behavior. With GWAS, thousands of DNA samples can be scanned for thousands of SNPs throughout the human genome, with the goal of identifying variations that modestly increase the risk of developing common diseases.

Unlike the candidate gene approach—which focuses on preselected genomic variations—GWAS scans the whole genome and may identify unexpected susceptibility factors. Unlike the family-based linkage approach, GWAS is not limited to specific families and can address all recombination events in a population.

 

Challenges are associated with GWAS, however, and include:

• need for substantial numbers (2,000 to 5,000) of rigorously described cases and matched controls
• need for accurate, high-throughput genotyping technologies and sophisticated algorithms for analyzing data
• risk of high false-positive rates related to multiple testing
• inability to scan 100% of the genome, which may lead to false-negative findings.

Table

Examples of gene variations related to alcohol misuse and alcoholism phenotypes

Phenotype	Gene variation(s)
Related to alcohol misuse
Low response/high tolerance to alcohol	L allele of serotonin transporter gene (SLC6A4) and Ser385 allele of alpha-6 subunit of GABAA receptor gene (GABRA6) in adolescents and healthy adult men;a,b 600G allele of alpha-2 subunit of GABAA receptor gene (GABRA2) in healthy social drinkersc
Cue-related craving for alcohol	118G allele of opioid μ-receptor gene (OMPR) and L allele of dopamine receptor type 4 gene (DRD4) in young problem drinkersd,e
Binge drinking	S allele of serotonin transporter gene in college students; combination of SS genotype of serotonin transporter gene and HH genotype of MAOA gene in young womenf
Related to alcoholism
Alcohol dependence	Two common haplotypes of GABRA2 geneg
Liver cirrhosis in alcoholics	-238A allele of tumor necrosis factor gene (TNFA)h
Protects against withdrawal symptoms in alcoholics	-141C Del variant of the dopamine receptor type 2 gene (DRD2)i
Associated with delirium tremens	8 genetic polymorphisms in 3 candidate genes involved in the dopamine transmission (DRD2, DRD3, and SLC6A3), 1 gene involved in the glutamate pathway (GRIK3), 1 neuropeptide gene (BDNF), and 1 cannabinoid gene (CNR1)j
Associated with alcohol withdrawal seizures	9 repeat allele of dopamine transporter (SLC6A3); 10 repeat allele of tyrosine hydroxylase gene (TH); Ser9 allele of dopamine receptor type 3 gene (DRD3); SS genotype of serotonin transporter gene; 2108A allele in NR1 subunit of NMDA receptor gene (GRIN1)k-m
GABAA: gamma-aminobutyric acid A; MAOA: monoamine oxidase A; NMDA: N-methyl-D-aspartate
Source: Click here to view references

Figure 3
2 ways to seek relationships between genes and behavior

Researchers use ‘forward’ and ‘reverse’ genetics to connect behavioral phenotypes with predisposing genotypes. Each approach must consider intermediary functional anatomic and physiologic levels (black box), as shown in this conceptual framework.
DA: dopamine; EEG: electroencephalography; 5-HT: serotonin; LTD: long-term depression; LTP: long-term potentiation; RNA: ribonucleic acid; SNPs: single nucleotide polymorphisms; VNTRs: variable number tandem (triplet) repeats

Clinical implications

Genomic research is increasing our understanding of alcohol’s pharmacokinetic and pharmacodynamic interactions and of potential genetic associations with alcoholic phenotypes. These insights may lead to discovery of new therapies to compensate for specific physiologic and behavioral dysfunctions. For example, medications with pharmacologic profiles complimentary to addiction-related physiologic/behavioral deficits might be designed in the future.

Likewise, new understandings about genetic variability may allow us to predict an individual’s ability to tolerate and respond to existing medications used to treat alcohol dependence. For example, in studies of alcoholic and nonalcoholic subjects:

• Individuals with the 118G variant allele of the μ-opioid receptor may experience a stronger subjective response to alcohol and respond more robustly to naltrexone treatment than do carriers of the more common 118A allele.³²
• Persons with a functional variation in the DRD4 gene (7 repeat allele–DRD4L) coding for type 4 dopamine receptor reported greater euphoria and reward while drinking alcohol and reduced alcohol consumption during 12-week treatment with olanzapine, a DRD2/DRD4 blocker.³³

Applying this approach to the study of acamprosate has been difficult because of uncertainty about which protein molecules it targets. Variation in the Per2 gene (coding for protein involved in the circadian cycle) has been shown to be associated with brain glutamate levels, alcohol consumption, and the effects of acamprosate, although these interactions require further investigation.³⁴

Pharmacogenomics of alcoholism treatment is in a very early stage of development. Findings require replication in different clinical samples and functional analysis. At the same time, if the reported association between the μ-opioid receptor genetic variation and naltrexone’s treatment efficacy is confirmed, this finding could help to guide clinical practice. Studies of genomic predictors of other medications’ efficacy and tolerability for alcoholism treatment would be expected to follow.

Related resources

• National Institute on Alcohol Abuse and Alcoholism. Collaborative Studies on Genetics of Alcoholism (COGA). www.niaaa.nih.gov (search NIAAA-funded collaborative research programs).
• Dick DM, Jones K, Saccone N, et al. Endophenotypes successfully lead to gene identification: results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet 2006;36(1):112-26.

Drug brand names

• Acamprosate • Campral
• Naltrexone • ReVia, Vivitrol
• Olanzapine • Zyprexa

Disclosure

 

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

Acknowledgments

This work has been supported by the S.C. Johnson Genomic of Addictions Program. The authors thank Ms. Barbara Hall for expert technical assistance in preparing this manuscript.

Children of alcoholics have a 40% to 60% increased risk of developing severe alcohol-related problems¹—a harsh legacy recognized for >30 years. Now, as the result of rapidly growing evidence, we can explain in greater detail why alcoholism runs in families when discussing alcohol dependence with patients.

Individuals vary in response to medications and substances of abuse, and genetic research is revealing the heritable origins. Numerous genetic variations are known to influence response to alcohol, as well as alcoholism’s pathophysiology, clinical manifestations, and treatment. Pieces are still missing from this complex picture, but investigators are identifying possible risk factors for alcoholism and matching potential responders with treatments such as naltrexone and acamprosate.

This article provides a progress report on contemporary genetic research of alcoholism. Our goal is to inform your clinical practice by describing:

• new understandings of the genetics of alcoholism
• how researchers identify relationships between genetic variations and clinical/behavioral phenomena
• practical implications of this knowledge.

Genetic variations and risk of addiction

No single gene appears to cause alcoholism. Many genetic variations that accumulated during evolution likely contribute to individual differences in response to alcohol and susceptibility to developing alcohol-related problems. A growing number of genetic variations have been associated with increased alcohol tolerance, consumption, and other related phenotypes.

Like other addictive substances, alcohol triggers pharmacodynamic effects by interacting with a variety of molecular targets (Figure 1).² These target proteins in turn interact with specific signaling proteins and trigger responses in complex functional pathways. Genetic variations may affect the structure of genes coding for proteins that constitute pathways involved in alcohol’s effects on target proteins (pharmacodynamics) or its metabolism (pharmacokinetics). If such variations alter the production, function, or stability of these proteins, the pathway’s function also may be altered and produce behavioral phenotypes—such as high or low sensitivity to alcohol’s effects.

Alcoholism-related phenotypes. DSM-IV-TR diagnostic criteria include some but not all of the multiple phenotypes within alcoholism’s clinical presentation. Researchers in the Collaborative Studies on Genetics of Alcoholism (COGA)³ identified chromosome regions linked to alcoholism-related phenotypes, including:

• alcohol dependence⁴
• later age of drinking onset and increased harm avoidance⁵
• alcoholism and depression⁶
• alcohol sensitivity⁷
• alcohol consumption.⁸

To identify genes of interest within these chromosome regions, researchers used transitional phenotypes (endophenotypes) that “lie on the pathway between genes and disease,”^9,10 and allowed them to characterize the neural systems affected by gene risk variants.¹¹ As a result, they found associations among variations in the GABRA2 gene, (encoding the alpha-2 subunit of the GABAA receptor), specific brain oscillations (electrophysiologic endophenotype), and predisposition to alcohol dependence.^12,13 By this same strategy, researchers discovered an association between the endophenotype (low-level of response to alcohol) and some genotypes, including at least 1 short allele of the serotonin transporter gene SLC6A4.¹⁴

Figure 1
Known molecular targets for alcohol and other drugs of abuse

Effects of drugs of abuse (black arrows) influence intracellular signaling pathways (blue arrows) to produce immediate and long-term changes in cell function.
cAMP: cyclic adenosine monophosphate; GABAA: gamma-aminobutyric acid A receptor; Gi, Gs, Gq: G proteins (heterotrimeric guanine nucleotide-binding proteins) MAPK: mitogen-activated protein kinase; N-cholino receptor: nicotinic cholinoreceptor; NMDA: N-methyl-D-aspartate; PKA: protein kinase A
Source: Created for CURRENT PSYCHIATRY from information in reference 2

Alcohol metabolism

Alcohol is metabolized to acetic acid through primary and auxiliary pathways involving alcohol and acetaldehyde dehydrogenases (ADH/ALDH) and the microsomal ethanol oxidizing system (cytochrome P-450 [CYP] 2E1)¹⁵ (Figure 2). Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol needed to be metabolized. Catalase and fatty acid ethyl ester synthases play a minor role under normal conditions but may be implicated in alcohol-induced organ damage.¹⁶

ADH/ALDH pathway. From one individual to another, the ability to metabolize ethyl alcohol varies up to 3- to 4-fold.¹⁷ In European and Amerindian samples, a genetic link has been identified between alcoholism and the 4q21-23 region on chromosome 4.¹⁸ This region contains a cluster of 7 genes encoding for alcohol dehydrogenases (ADH), including 3 Class I genes—ADH1A, ADH1B, and ADH1C—coding for the corresponding proteins that play a major role in alcohol metabolism.¹⁹ In eastern Asian samples, alleles encoding high activity enzymes (ADH1B*47His and ADH1C*349Ile) are significantly less frequent in alcoholics compared with nonalcoholic controls.²⁰

Mitochondrial ALDH2 protein plays the central role in acetaldehyde metabolism and is highly expressed in the liver, stomach, and other tissues—including the brain.²¹ The ALDH2*2 gene variant encodes for a catalytically inactive enzyme, thus inhibiting acetaldehyde metabolism and causing a facial flushing reaction.²² The ALDH2*2 allele has a relatively high frequency in Asians but also is found in other populations.²³ Meta-analyses of published data indicate that possessing either of the variant alleles in the ADH1B and ALDH2 genes is protective against alcohol dependence in Asians.²⁴

 

The ADH4 enzyme catalyzes oxidation or reduction of numerous substrates—including long-chain aliphatic alcohols and aromatic aldehydes—and becomes involved in alcohol metabolism at moderate to high concentrations. The -75A allele of the ADH4 gene has promoter activity more than twice that of the -75C allele and significantly affects its expression.²⁵ This substitution in the promoter region, as well as A/G SNP (rs1042364)—a single nucleotide polymorphism (SNP)—at exon 9, has been associated with an increased risk for alcohol and drug dependence in European Americans.²⁶

Finally, variations in the ADH7 gene may play a protective role against alcoholism through epistatic effects.²⁷

The CYP 2E1 pathway has low initial catalytic efficiency compared with the ADH/ALDH pathway, but it may metabolize alcohol up to 10 times faster after chronic alcohol consumption or cigarette smoking and accounts for metabolic tolerance.²⁸ CYP 2E1 is involved in metabolizing both alcohol and acetaldehyde.²⁹ The CYP 2E1*1D polymorphism has been associated with greater inducibility as well as alcohol and nicotine dependence.³⁰

Thus, linkage and association studies support the association of phenotypes related to alcohol response and dependence with variations in genes that code for proteins involved in alcohol’s pharmacodynamic and pharmacokinetic effects. Each of these findings is important, but conceptual models organizing them all and explaining their role in alcohol’s effects and predisposition to alcoholism have yet to be constructed.

Figure 2
Genetic variations that affect alcohol metabolism pathways

Genetic variations affect the efficiency of primary and auxiliary pathways by which ethyl alcohol is metabolized to acetaldehyde and acetic acid. Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol to be metabolized.
ADH: alcohol dehydrogenase; ALDH: acetaldehyde dehydrogenase; P450CYP 2E1: cytochrome P450, family 2, subfamily E, polypeptide 1; A/G SNP: adenine/guanine single nucleotide polymorphism

Phenotype-genotype relationships

Alcohol—unlike most other addictive substances—does not have a specific receptor and is believed to act by disturbing the balance between excitatory and inhibitory neurotransmission in the neural system. Consequently, researchers explore relationships between genetics and alcohol-related problems using 2 approaches:

• Forward genetics (discovering disease-related genes via genome-wide studies and then studying their function; examples include linkage and genome-wide association studies [GWAS]).
• Reverse genetics (testing whether candidate genes and polymorphisms identified in animal studies as relevant for biological effects also exist in humans and are relevant to the phenotype).³¹

When searching for relationships between genotypes and phenotypes, both approaches must take into account a framework of functional anatomic and physiologic connections (Figure 3).

Linkage studies. The goal of linkage studies is to find a link between a phenotypic variation (ideally a measurable trait, such as number of drinks necessary for intoxication) and the chromosomal marker expected to be in the vicinity of the disease-specific gene variation. An advantage of linkage studies is that they can be started without knowing specific DNA sequences. Their limitations include:

• limited power when applied to complex diseases such as alcoholism
• they do not yield gene-specific information
• their success is highly dependent on family members’ willingness to participate.

Association studies. Candidate gene-based association studies are designed to directly test a potential association between the phenotype of interest and a known genomic sequence variation. This approach provides adequate power to study variations with modest effects and allows use of DNA from unrelated individuals. The candidate gene approach has revealed associations between specific genomic variations and phenotypes related to alcohol misuse and alcoholism (Table).

Like linkage studies, association studies have their own challenges and limitations, such as:

• historically high false-positive rates
• confounding risks (allele frequencies may vary because of ethnic stratification rather than disease predisposition).

To address these challenges, researchers must carefully choose behavioral, physiologic, or intermediate phenotypes and genotype variations, as well as control subjects and sample sizes. Replication studies are necessary to rule out false-positive associations. In fact, only some of the findings depicted in the Table—those related to GABRA2 and GABRA6 and few other genes—have been replicated.

Genome-wide association studies are a powerful new method for studying relationships between genomic variability and behavior. With GWAS, thousands of DNA samples can be scanned for thousands of SNPs throughout the human genome, with the goal of identifying variations that modestly increase the risk of developing common diseases.

Unlike the candidate gene approach—which focuses on preselected genomic variations—GWAS scans the whole genome and may identify unexpected susceptibility factors. Unlike the family-based linkage approach, GWAS is not limited to specific families and can address all recombination events in a population.

 

Challenges are associated with GWAS, however, and include:

• need for substantial numbers (2,000 to 5,000) of rigorously described cases and matched controls
• need for accurate, high-throughput genotyping technologies and sophisticated algorithms for analyzing data
• risk of high false-positive rates related to multiple testing
• inability to scan 100% of the genome, which may lead to false-negative findings.

Table

Examples of gene variations related to alcohol misuse and alcoholism phenotypes

Phenotype	Gene variation(s)
Related to alcohol misuse
Low response/high tolerance to alcohol	L allele of serotonin transporter gene (SLC6A4) and Ser385 allele of alpha-6 subunit of GABAA receptor gene (GABRA6) in adolescents and healthy adult men;a,b 600G allele of alpha-2 subunit of GABAA receptor gene (GABRA2) in healthy social drinkersc
Cue-related craving for alcohol	118G allele of opioid μ-receptor gene (OMPR) and L allele of dopamine receptor type 4 gene (DRD4) in young problem drinkersd,e
Binge drinking	S allele of serotonin transporter gene in college students; combination of SS genotype of serotonin transporter gene and HH genotype of MAOA gene in young womenf
Related to alcoholism
Alcohol dependence	Two common haplotypes of GABRA2 geneg
Liver cirrhosis in alcoholics	-238A allele of tumor necrosis factor gene (TNFA)h
Protects against withdrawal symptoms in alcoholics	-141C Del variant of the dopamine receptor type 2 gene (DRD2)i
Associated with delirium tremens	8 genetic polymorphisms in 3 candidate genes involved in the dopamine transmission (DRD2, DRD3, and SLC6A3), 1 gene involved in the glutamate pathway (GRIK3), 1 neuropeptide gene (BDNF), and 1 cannabinoid gene (CNR1)j
Associated with alcohol withdrawal seizures	9 repeat allele of dopamine transporter (SLC6A3); 10 repeat allele of tyrosine hydroxylase gene (TH); Ser9 allele of dopamine receptor type 3 gene (DRD3); SS genotype of serotonin transporter gene; 2108A allele in NR1 subunit of NMDA receptor gene (GRIN1)k-m
GABAA: gamma-aminobutyric acid A; MAOA: monoamine oxidase A; NMDA: N-methyl-D-aspartate
Source: Click here to view references

Figure 3
2 ways to seek relationships between genes and behavior

Researchers use ‘forward’ and ‘reverse’ genetics to connect behavioral phenotypes with predisposing genotypes. Each approach must consider intermediary functional anatomic and physiologic levels (black box), as shown in this conceptual framework.
DA: dopamine; EEG: electroencephalography; 5-HT: serotonin; LTD: long-term depression; LTP: long-term potentiation; RNA: ribonucleic acid; SNPs: single nucleotide polymorphisms; VNTRs: variable number tandem (triplet) repeats

Clinical implications

Genomic research is increasing our understanding of alcohol’s pharmacokinetic and pharmacodynamic interactions and of potential genetic associations with alcoholic phenotypes. These insights may lead to discovery of new therapies to compensate for specific physiologic and behavioral dysfunctions. For example, medications with pharmacologic profiles complimentary to addiction-related physiologic/behavioral deficits might be designed in the future.

Likewise, new understandings about genetic variability may allow us to predict an individual’s ability to tolerate and respond to existing medications used to treat alcohol dependence. For example, in studies of alcoholic and nonalcoholic subjects:

• Individuals with the 118G variant allele of the μ-opioid receptor may experience a stronger subjective response to alcohol and respond more robustly to naltrexone treatment than do carriers of the more common 118A allele.³²
• Persons with a functional variation in the DRD4 gene (7 repeat allele–DRD4L) coding for type 4 dopamine receptor reported greater euphoria and reward while drinking alcohol and reduced alcohol consumption during 12-week treatment with olanzapine, a DRD2/DRD4 blocker.³³

Applying this approach to the study of acamprosate has been difficult because of uncertainty about which protein molecules it targets. Variation in the Per2 gene (coding for protein involved in the circadian cycle) has been shown to be associated with brain glutamate levels, alcohol consumption, and the effects of acamprosate, although these interactions require further investigation.³⁴

Pharmacogenomics of alcoholism treatment is in a very early stage of development. Findings require replication in different clinical samples and functional analysis. At the same time, if the reported association between the μ-opioid receptor genetic variation and naltrexone’s treatment efficacy is confirmed, this finding could help to guide clinical practice. Studies of genomic predictors of other medications’ efficacy and tolerability for alcoholism treatment would be expected to follow.

Related resources

• National Institute on Alcohol Abuse and Alcoholism. Collaborative Studies on Genetics of Alcoholism (COGA). www.niaaa.nih.gov (search NIAAA-funded collaborative research programs).
• Dick DM, Jones K, Saccone N, et al. Endophenotypes successfully lead to gene identification: results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet 2006;36(1):112-26.

Drug brand names

• Acamprosate • Campral
• Naltrexone • ReVia, Vivitrol
• Olanzapine • Zyprexa

Disclosure

 

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

Acknowledgments

This work has been supported by the S.C. Johnson Genomic of Addictions Program. The authors thank Ms. Barbara Hall for expert technical assistance in preparing this manuscript.