Current Psychiatry

Three years after the U.S.-led invasion of Iraq, psychiatrists on the home front are dealing with the war’s neuropsychiatric casualties. We are seeing veterans, their families, friends, and acquaintances, whether we practice in VA medical centers, military medicine, or the community.

To help us, Drs. Timothy Lineberry, Sriram Ramaswamy, J. Michael Bostwick, and James Rundell offer tools to screen for and treat combat-related posttraumatic stress disorder, including PTSD of military sexual trauma. Dr. John Daniels tells which medications may do more harm than good for patients with traumatic brain injury.

World War II brought psychiatric disorders home, showing that not just “crazy people” develop psychiatric symptoms. A half-million U.S. troops were admitted for psychiatric care in overseas hospitals alone.¹ Americans began to accept that anyone under extreme conditions could become psychiatrically ill.

Today, there are many ways to feel about our involvement in “Operation Iraqi Freedom” but only one way to feel about the dedicated men and women serving there. They deserve our respect, our love, and all our knowledge and skill to help them deal with the trauma they have endured for us all.

Three years after the U.S.-led invasion of Iraq, psychiatrists on the home front are dealing with the war’s neuropsychiatric casualties. We are seeing veterans, their families, friends, and acquaintances, whether we practice in VA medical centers, military medicine, or the community.

To help us, Drs. Timothy Lineberry, Sriram Ramaswamy, J. Michael Bostwick, and James Rundell offer tools to screen for and treat combat-related posttraumatic stress disorder, including PTSD of military sexual trauma. Dr. John Daniels tells which medications may do more harm than good for patients with traumatic brain injury.

World War II brought psychiatric disorders home, showing that not just “crazy people” develop psychiatric symptoms. A half-million U.S. troops were admitted for psychiatric care in overseas hospitals alone.¹ Americans began to accept that anyone under extreme conditions could become psychiatrically ill.

Today, there are many ways to feel about our involvement in “Operation Iraqi Freedom” but only one way to feel about the dedicated men and women serving there. They deserve our respect, our love, and all our knowledge and skill to help them deal with the trauma they have endured for us all.

Three years after the U.S.-led invasion of Iraq, psychiatrists on the home front are dealing with the war’s neuropsychiatric casualties. We are seeing veterans, their families, friends, and acquaintances, whether we practice in VA medical centers, military medicine, or the community.

To help us, Drs. Timothy Lineberry, Sriram Ramaswamy, J. Michael Bostwick, and James Rundell offer tools to screen for and treat combat-related posttraumatic stress disorder, including PTSD of military sexual trauma. Dr. John Daniels tells which medications may do more harm than good for patients with traumatic brain injury.

World War II brought psychiatric disorders home, showing that not just “crazy people” develop psychiatric symptoms. A half-million U.S. troops were admitted for psychiatric care in overseas hospitals alone.¹ Americans began to accept that anyone under extreme conditions could become psychiatrically ill.

Today, there are many ways to feel about our involvement in “Operation Iraqi Freedom” but only one way to feel about the dedicated men and women serving there. They deserve our respect, our love, and all our knowledge and skill to help them deal with the trauma they have endured for us all.

Tiberius Claudius Germanicus, age 64 and the third emperor of Rome’s Julio-Claudian dynasty, presents to you and reports, “I have severe stomach cramps. I think my wife is poisoning me, but no one believes me. I need your help.”

Retrospective diagnoses are difficult and sometimes ill-advised, but pondering the psychiatric diagnoses of historical figures can alert us to possible differential diagnoses in today’s patients. Consider this imaginary interview between Claudius and a psychiatrist, which suggests several possible diagnoses.

History: terrible royal childhood

Though born into royalty, Claudius was such a sickly infant that his family was ashamed of him and kept him out of their home. He was raised by servants. As a child, he limped and was ridiculed.

He tells you he received little formal education but had many tutors. He learned several languages and became a distinguished historian, scholar, and writer. He served in the military, both in Rome and overseas. For 13 years he has ruled the Roman Empire but fears he will soon be overthrown.

Claudius’ reign began well. He treated his freedmen advisors well, diligently attended to court proceedings, built an aqueduct, and reorganized the Roman government. Recently, however, he has ruled more eccentrically and harshly. He has ordered capricious and costly public works, such as the futile attempt to drain the 12-mile-long Fucine Lake so that the land could be farmed. He has become fond of gladiatorial games and enjoys ordering the execution of political foes. He drinks several liters of wine daily and gorges himself at imperial banquets.

This patient’s family history is complex (Box) and fraught with antisocial behavior and mental illness. Three previous marriages failed, and he describes his current wife, Agrippina, as powerful and manipulative. She has a son, Nero, from an earlier marriage. Claudius fears being poisoned by Agrippina after she instigates a relationship between Nero and Claudius’ daughter.

Box

Interview: ‘surrounded by enemies’

Claudius is uncooperative during the interview. He is irritable, tends to bark orders, smells of alcohol, stutters severely, and drools. He admits that he is depressed over myriad family problems.

He also believes that he will become a deity when he dies. He reminds you that he has the power to order executions and wonders if he should have Agrippina and her minions killed. He claims to have written 43 books and numerous historical monographs and to be the last person in the world to speak fluent Etruscan, but laments that no one appreciates his scholarly work. He says he is “surrounded by enemies” and rambles on about family intrigue, cabals, and executions.

He is oriented and shows no florid psychotic symptoms or signs of suicidality. His insight and judgment are severely impaired, and he rejects the idea that he might have a psychiatric disorder.

Claudius refuses a physical exam and abruptly terminates the interview after about 20 minutes, saying he must attend to important affairs of state.

Follow-up: claudius’ ‘last supper’

You want to get more information from family members but wonder if it is safe to do so. It becomes moot: Claudius dies one evening at dinner, days after the interview.

poll here

The authors’ observations

Lead poisoning can cause a range of medical and neuropsychological problems, including attention deficits, antisocial behavior, and irritability.^1-4 Romans—particularly the upper class—were exposed to lead from numerous sources:

• Drinking water was contaminated because lead was used extensively to build ancient Rome’s water transportation systems.
  
• Grape juice fermented to become wine was often preserved in lead vessels, which made it sweeter. The elite drank wine more profusely than did lower-class Romans, who probably could not afford wine. Lead-sweetened grape juice was also used in delicacies eaten by the wealthy.
  
• The rich also favored expensive, lead-lined bronze bowls and plates, whereas commoners used cheap earthenware. Thus, ancient Rome’s ruling class was ingesting lead-contaminated drink and food.
  

Jerome Nriagu, a geochemist who has studied lead’s toxic effects, attributed many of Claudius’ symptoms and negative traits to lead poisoning: “He had disturbed speech, weak limbs, an ungainly gait, tremors, fits of excessive and inappropriate laughter, and unseemly anger, and he often slobbered…his contracting of plumbism would not be surprising, since he was an intemperate glutton.”⁶ Nriagu also argued that the neuropsychological sequelae of lead poisoning might have clouded the judgment of many Roman emperors.⁶

Yet some scholars, notably Robert Graves,^7,8 have argued that Claudius was highly intelligent and that his copious writing showcased his scholarly interests, hard work, and sound judgment in young adulthood. Based on Graves’ assessment, Claudius probably did not suffer severe plumbism as a child.

Birth injury or cerebral palsy might have caused Claudius’ poor gait and drooling, which were present from childhood. As his drinking and gluttony worsened later in life, alcoholism and lead poisoning could have shortened Claudius’ temper and blurred his judgment, particularly in marrying Agrippina.

Claudius’ belief that he would become a god does not strongly indicate psychosis, because his contemporaries believed that emperors could be deified after death. Opler et al,⁹ however, found that prenatal lead exposure, as suggested by elevated D-aminolevulinic acid, may be a risk factor for schizophrenia and other psychiatric disorders that manifest in late adolescence or adulthood.

Although we know little about Claudius’ medical problems, abdominal pain has a broad differential diagnosis. Poisoning at Agrippina’s hands or alcohol-induced gastritis, as well as lead-induced abdominal colic, could have caused his intolerable pain.

Bipolar disorder. Claudius’ unrestrained spending, irritability, impulsivity, grandiosity, and mood lability suggest bipolar disorder. Hypomania could have fueled his vast literary output, which has been lost. His belief that he would be deified could also be a manic symptom.

Hypomania was prevalent among Claudius’ family. Two close relatives—his nephew Caligula and great-nephew/adopted son Nero—had marked mood swings. These two emperors were more antisocial than Claudius and showed behavior more consistent with frank mania.

Caligula, who preceded Claudius as emperor, was well known for his excessive behaviors. He was vicious and promiscuous, having sex in public with men, wives of others, and his sisters. Most famously, he considered making his horse, Incitatus, a consul. He gave this horse a “marble stable…a house and a household of slaves and furniture.”¹⁰

Nero, who succeeded Claudius, was an alcoholic who frequently indulged his appetites. He believed he was a great singer and became infamous for playing his fiddle while Rome burned. Some of his last words are supposed to have been, “What an artist dies with me!”¹⁰

Alcoholism. Some historians have estimated that two-thirds of Roman emperors who reigned from 30 BC (Augustus) to 220 AD (Elegabalus) drank heavily.⁶ Claudius was reputedly a heavy drinker, and many features displayed by him and his relatives—bad temper, poor judgment, paranoia, impulsivity, violence, and sexual indiscretions—can result from alcohol abuse.

Psychosocial stressors. Claudius was raised and surrounded by malevolent people, then given almost limitless power. That mix of circumstances, plus fear fostered by persistent intrigue, may explain some of his behavior, particularly his brutality.

poll here

The authors’ observations

Had laboratories been available in ancient Rome, a blood test would have determined whether Claudius suffered lead poisoning. Diagnosing bipolar disorder and/or alcoholism is much more difficult. Differentiating these disorders from each other and from other psychiatric disorders is challenging, as no laboratory tests confirm the diagnosis. Ongoing clinical observation of the illness and response to medication are crucial.

In some cases, having the patient list his or her depressive and manic episodes on a “life chart” might clarify the diagnosis. This exercise can also help the patient recognize bipolar symptoms and accept that he or she has the illness, which is critical to ensuring treatment adherence. Also start medication at this time.

Treatment

Treat bipolar disorder and alcoholism simultaneously, as either disorder could worsen the other’s course.^11,12

Lithium or valproate would be probable first-line treatments for Claudius. Discuss the medication’s risks and benefits with the patient and involved family members/caretakers. Inform them that you might have to change or add medication if the patient does not respond or experiences side effects.

Psychotherapy and/or psychoeducation are integral to treating comorbid bipolar disorder and alcoholism. Claudius also could have benefited from:

• education about healthy dieting
  
• counseling against high-risk behaviors associated with alcoholism, such as domestic violence and gambling
  
• a support group for patients with bipolar disorder or a 12-step program.
  

What claudius can teach us

Although Claudius’ symptoms cannot be diagnosed with certainty, the information and perspective available today offer insight into his likely psychiatric problems. His case reminds us that:

• Patients often have multiple diagnoses. Bipolar disorder is strongly associated with substance abuse disorder—particularly alcoholism.
  
• Lead-containing alcoholic beverages are still a public health concern. Morgan et al¹³ tested 115 samples of moonshine from nine southeastern, south central, and north central U.S. states. One-third of samples contained lead >300 μg/dL. The authors estimated that excessive consumption of 25% of the samples could lead to blood lead levels consistent with lead poisoning (≥25 μg/dL).
  

Related resources

• Schwartz BS, Stewart WF, Bolla KO, et al. Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology 2000;55:1144-50.
  
• Canfield RL, Henderson CR Jr, Cory-Slechta DA, et al. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 2003;348:1517-26.
  
• Salloum IM, Thase ME. Impact of substance abuse on the course and treatment of bipolar disorder. Bipolar Disord 2000;2:269-80.
  
• Nriagu JO. Lead and lead poisoning in antiquity. New York: John Wiley and Sons; 1983.
  

• Lithium • Eskalith, others
  
• Valproate • Depakene
  

Dr. Frankenburg reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Tiberius Claudius Germanicus, age 64 and the third emperor of Rome’s Julio-Claudian dynasty, presents to you and reports, “I have severe stomach cramps. I think my wife is poisoning me, but no one believes me. I need your help.”

Retrospective diagnoses are difficult and sometimes ill-advised, but pondering the psychiatric diagnoses of historical figures can alert us to possible differential diagnoses in today’s patients. Consider this imaginary interview between Claudius and a psychiatrist, which suggests several possible diagnoses.

History: terrible royal childhood

Though born into royalty, Claudius was such a sickly infant that his family was ashamed of him and kept him out of their home. He was raised by servants. As a child, he limped and was ridiculed.

He tells you he received little formal education but had many tutors. He learned several languages and became a distinguished historian, scholar, and writer. He served in the military, both in Rome and overseas. For 13 years he has ruled the Roman Empire but fears he will soon be overthrown.

Claudius’ reign began well. He treated his freedmen advisors well, diligently attended to court proceedings, built an aqueduct, and reorganized the Roman government. Recently, however, he has ruled more eccentrically and harshly. He has ordered capricious and costly public works, such as the futile attempt to drain the 12-mile-long Fucine Lake so that the land could be farmed. He has become fond of gladiatorial games and enjoys ordering the execution of political foes. He drinks several liters of wine daily and gorges himself at imperial banquets.

This patient’s family history is complex (Box) and fraught with antisocial behavior and mental illness. Three previous marriages failed, and he describes his current wife, Agrippina, as powerful and manipulative. She has a son, Nero, from an earlier marriage. Claudius fears being poisoned by Agrippina after she instigates a relationship between Nero and Claudius’ daughter.

Box

Interview: ‘surrounded by enemies’

Claudius is uncooperative during the interview. He is irritable, tends to bark orders, smells of alcohol, stutters severely, and drools. He admits that he is depressed over myriad family problems.

He also believes that he will become a deity when he dies. He reminds you that he has the power to order executions and wonders if he should have Agrippina and her minions killed. He claims to have written 43 books and numerous historical monographs and to be the last person in the world to speak fluent Etruscan, but laments that no one appreciates his scholarly work. He says he is “surrounded by enemies” and rambles on about family intrigue, cabals, and executions.

He is oriented and shows no florid psychotic symptoms or signs of suicidality. His insight and judgment are severely impaired, and he rejects the idea that he might have a psychiatric disorder.

Claudius refuses a physical exam and abruptly terminates the interview after about 20 minutes, saying he must attend to important affairs of state.

Follow-up: claudius’ ‘last supper’

You want to get more information from family members but wonder if it is safe to do so. It becomes moot: Claudius dies one evening at dinner, days after the interview.

poll here

The authors’ observations

Lead poisoning can cause a range of medical and neuropsychological problems, including attention deficits, antisocial behavior, and irritability.^1-4 Romans—particularly the upper class—were exposed to lead from numerous sources:

• Drinking water was contaminated because lead was used extensively to build ancient Rome’s water transportation systems.
  
• Grape juice fermented to become wine was often preserved in lead vessels, which made it sweeter. The elite drank wine more profusely than did lower-class Romans, who probably could not afford wine. Lead-sweetened grape juice was also used in delicacies eaten by the wealthy.
  
• The rich also favored expensive, lead-lined bronze bowls and plates, whereas commoners used cheap earthenware. Thus, ancient Rome’s ruling class was ingesting lead-contaminated drink and food.
  

Jerome Nriagu, a geochemist who has studied lead’s toxic effects, attributed many of Claudius’ symptoms and negative traits to lead poisoning: “He had disturbed speech, weak limbs, an ungainly gait, tremors, fits of excessive and inappropriate laughter, and unseemly anger, and he often slobbered…his contracting of plumbism would not be surprising, since he was an intemperate glutton.”⁶ Nriagu also argued that the neuropsychological sequelae of lead poisoning might have clouded the judgment of many Roman emperors.⁶

Yet some scholars, notably Robert Graves,^7,8 have argued that Claudius was highly intelligent and that his copious writing showcased his scholarly interests, hard work, and sound judgment in young adulthood. Based on Graves’ assessment, Claudius probably did not suffer severe plumbism as a child.

Birth injury or cerebral palsy might have caused Claudius’ poor gait and drooling, which were present from childhood. As his drinking and gluttony worsened later in life, alcoholism and lead poisoning could have shortened Claudius’ temper and blurred his judgment, particularly in marrying Agrippina.

Claudius’ belief that he would become a god does not strongly indicate psychosis, because his contemporaries believed that emperors could be deified after death. Opler et al,⁹ however, found that prenatal lead exposure, as suggested by elevated D-aminolevulinic acid, may be a risk factor for schizophrenia and other psychiatric disorders that manifest in late adolescence or adulthood.

Although we know little about Claudius’ medical problems, abdominal pain has a broad differential diagnosis. Poisoning at Agrippina’s hands or alcohol-induced gastritis, as well as lead-induced abdominal colic, could have caused his intolerable pain.

Bipolar disorder. Claudius’ unrestrained spending, irritability, impulsivity, grandiosity, and mood lability suggest bipolar disorder. Hypomania could have fueled his vast literary output, which has been lost. His belief that he would be deified could also be a manic symptom.

Hypomania was prevalent among Claudius’ family. Two close relatives—his nephew Caligula and great-nephew/adopted son Nero—had marked mood swings. These two emperors were more antisocial than Claudius and showed behavior more consistent with frank mania.

Caligula, who preceded Claudius as emperor, was well known for his excessive behaviors. He was vicious and promiscuous, having sex in public with men, wives of others, and his sisters. Most famously, he considered making his horse, Incitatus, a consul. He gave this horse a “marble stable…a house and a household of slaves and furniture.”¹⁰

Nero, who succeeded Claudius, was an alcoholic who frequently indulged his appetites. He believed he was a great singer and became infamous for playing his fiddle while Rome burned. Some of his last words are supposed to have been, “What an artist dies with me!”¹⁰

Alcoholism. Some historians have estimated that two-thirds of Roman emperors who reigned from 30 BC (Augustus) to 220 AD (Elegabalus) drank heavily.⁶ Claudius was reputedly a heavy drinker, and many features displayed by him and his relatives—bad temper, poor judgment, paranoia, impulsivity, violence, and sexual indiscretions—can result from alcohol abuse.

Psychosocial stressors. Claudius was raised and surrounded by malevolent people, then given almost limitless power. That mix of circumstances, plus fear fostered by persistent intrigue, may explain some of his behavior, particularly his brutality.

poll here

The authors’ observations

Had laboratories been available in ancient Rome, a blood test would have determined whether Claudius suffered lead poisoning. Diagnosing bipolar disorder and/or alcoholism is much more difficult. Differentiating these disorders from each other and from other psychiatric disorders is challenging, as no laboratory tests confirm the diagnosis. Ongoing clinical observation of the illness and response to medication are crucial.

In some cases, having the patient list his or her depressive and manic episodes on a “life chart” might clarify the diagnosis. This exercise can also help the patient recognize bipolar symptoms and accept that he or she has the illness, which is critical to ensuring treatment adherence. Also start medication at this time.

Treatment

Treat bipolar disorder and alcoholism simultaneously, as either disorder could worsen the other’s course.^11,12

Lithium or valproate would be probable first-line treatments for Claudius. Discuss the medication’s risks and benefits with the patient and involved family members/caretakers. Inform them that you might have to change or add medication if the patient does not respond or experiences side effects.

Psychotherapy and/or psychoeducation are integral to treating comorbid bipolar disorder and alcoholism. Claudius also could have benefited from:

• education about healthy dieting
  
• counseling against high-risk behaviors associated with alcoholism, such as domestic violence and gambling
  
• a support group for patients with bipolar disorder or a 12-step program.
  

What claudius can teach us

Although Claudius’ symptoms cannot be diagnosed with certainty, the information and perspective available today offer insight into his likely psychiatric problems. His case reminds us that:

• Patients often have multiple diagnoses. Bipolar disorder is strongly associated with substance abuse disorder—particularly alcoholism.
  
• Lead-containing alcoholic beverages are still a public health concern. Morgan et al¹³ tested 115 samples of moonshine from nine southeastern, south central, and north central U.S. states. One-third of samples contained lead >300 μg/dL. The authors estimated that excessive consumption of 25% of the samples could lead to blood lead levels consistent with lead poisoning (≥25 μg/dL).
  

Related resources

• Schwartz BS, Stewart WF, Bolla KO, et al. Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology 2000;55:1144-50.
  
• Canfield RL, Henderson CR Jr, Cory-Slechta DA, et al. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 2003;348:1517-26.
  
• Salloum IM, Thase ME. Impact of substance abuse on the course and treatment of bipolar disorder. Bipolar Disord 2000;2:269-80.
  
• Nriagu JO. Lead and lead poisoning in antiquity. New York: John Wiley and Sons; 1983.
  

• Lithium • Eskalith, others
  
• Valproate • Depakene
  

Dr. Frankenburg reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Tiberius Claudius Germanicus, age 64 and the third emperor of Rome’s Julio-Claudian dynasty, presents to you and reports, “I have severe stomach cramps. I think my wife is poisoning me, but no one believes me. I need your help.”

Retrospective diagnoses are difficult and sometimes ill-advised, but pondering the psychiatric diagnoses of historical figures can alert us to possible differential diagnoses in today’s patients. Consider this imaginary interview between Claudius and a psychiatrist, which suggests several possible diagnoses.

History: terrible royal childhood

Though born into royalty, Claudius was such a sickly infant that his family was ashamed of him and kept him out of their home. He was raised by servants. As a child, he limped and was ridiculed.

He tells you he received little formal education but had many tutors. He learned several languages and became a distinguished historian, scholar, and writer. He served in the military, both in Rome and overseas. For 13 years he has ruled the Roman Empire but fears he will soon be overthrown.

Claudius’ reign began well. He treated his freedmen advisors well, diligently attended to court proceedings, built an aqueduct, and reorganized the Roman government. Recently, however, he has ruled more eccentrically and harshly. He has ordered capricious and costly public works, such as the futile attempt to drain the 12-mile-long Fucine Lake so that the land could be farmed. He has become fond of gladiatorial games and enjoys ordering the execution of political foes. He drinks several liters of wine daily and gorges himself at imperial banquets.

This patient’s family history is complex (Box) and fraught with antisocial behavior and mental illness. Three previous marriages failed, and he describes his current wife, Agrippina, as powerful and manipulative. She has a son, Nero, from an earlier marriage. Claudius fears being poisoned by Agrippina after she instigates a relationship between Nero and Claudius’ daughter.

Box

Interview: ‘surrounded by enemies’

Claudius is uncooperative during the interview. He is irritable, tends to bark orders, smells of alcohol, stutters severely, and drools. He admits that he is depressed over myriad family problems.

He also believes that he will become a deity when he dies. He reminds you that he has the power to order executions and wonders if he should have Agrippina and her minions killed. He claims to have written 43 books and numerous historical monographs and to be the last person in the world to speak fluent Etruscan, but laments that no one appreciates his scholarly work. He says he is “surrounded by enemies” and rambles on about family intrigue, cabals, and executions.

He is oriented and shows no florid psychotic symptoms or signs of suicidality. His insight and judgment are severely impaired, and he rejects the idea that he might have a psychiatric disorder.

Claudius refuses a physical exam and abruptly terminates the interview after about 20 minutes, saying he must attend to important affairs of state.

Follow-up: claudius’ ‘last supper’

You want to get more information from family members but wonder if it is safe to do so. It becomes moot: Claudius dies one evening at dinner, days after the interview.

poll here

The authors’ observations

Lead poisoning can cause a range of medical and neuropsychological problems, including attention deficits, antisocial behavior, and irritability.^1-4 Romans—particularly the upper class—were exposed to lead from numerous sources:

• Drinking water was contaminated because lead was used extensively to build ancient Rome’s water transportation systems.
  
• Grape juice fermented to become wine was often preserved in lead vessels, which made it sweeter. The elite drank wine more profusely than did lower-class Romans, who probably could not afford wine. Lead-sweetened grape juice was also used in delicacies eaten by the wealthy.
  
• The rich also favored expensive, lead-lined bronze bowls and plates, whereas commoners used cheap earthenware. Thus, ancient Rome’s ruling class was ingesting lead-contaminated drink and food.
  

Jerome Nriagu, a geochemist who has studied lead’s toxic effects, attributed many of Claudius’ symptoms and negative traits to lead poisoning: “He had disturbed speech, weak limbs, an ungainly gait, tremors, fits of excessive and inappropriate laughter, and unseemly anger, and he often slobbered…his contracting of plumbism would not be surprising, since he was an intemperate glutton.”⁶ Nriagu also argued that the neuropsychological sequelae of lead poisoning might have clouded the judgment of many Roman emperors.⁶

Yet some scholars, notably Robert Graves,^7,8 have argued that Claudius was highly intelligent and that his copious writing showcased his scholarly interests, hard work, and sound judgment in young adulthood. Based on Graves’ assessment, Claudius probably did not suffer severe plumbism as a child.

Birth injury or cerebral palsy might have caused Claudius’ poor gait and drooling, which were present from childhood. As his drinking and gluttony worsened later in life, alcoholism and lead poisoning could have shortened Claudius’ temper and blurred his judgment, particularly in marrying Agrippina.

Claudius’ belief that he would become a god does not strongly indicate psychosis, because his contemporaries believed that emperors could be deified after death. Opler et al,⁹ however, found that prenatal lead exposure, as suggested by elevated D-aminolevulinic acid, may be a risk factor for schizophrenia and other psychiatric disorders that manifest in late adolescence or adulthood.

Although we know little about Claudius’ medical problems, abdominal pain has a broad differential diagnosis. Poisoning at Agrippina’s hands or alcohol-induced gastritis, as well as lead-induced abdominal colic, could have caused his intolerable pain.

Bipolar disorder. Claudius’ unrestrained spending, irritability, impulsivity, grandiosity, and mood lability suggest bipolar disorder. Hypomania could have fueled his vast literary output, which has been lost. His belief that he would be deified could also be a manic symptom.

Hypomania was prevalent among Claudius’ family. Two close relatives—his nephew Caligula and great-nephew/adopted son Nero—had marked mood swings. These two emperors were more antisocial than Claudius and showed behavior more consistent with frank mania.

Caligula, who preceded Claudius as emperor, was well known for his excessive behaviors. He was vicious and promiscuous, having sex in public with men, wives of others, and his sisters. Most famously, he considered making his horse, Incitatus, a consul. He gave this horse a “marble stable…a house and a household of slaves and furniture.”¹⁰

Nero, who succeeded Claudius, was an alcoholic who frequently indulged his appetites. He believed he was a great singer and became infamous for playing his fiddle while Rome burned. Some of his last words are supposed to have been, “What an artist dies with me!”¹⁰

Alcoholism. Some historians have estimated that two-thirds of Roman emperors who reigned from 30 BC (Augustus) to 220 AD (Elegabalus) drank heavily.⁶ Claudius was reputedly a heavy drinker, and many features displayed by him and his relatives—bad temper, poor judgment, paranoia, impulsivity, violence, and sexual indiscretions—can result from alcohol abuse.

Psychosocial stressors. Claudius was raised and surrounded by malevolent people, then given almost limitless power. That mix of circumstances, plus fear fostered by persistent intrigue, may explain some of his behavior, particularly his brutality.

poll here

The authors’ observations

Had laboratories been available in ancient Rome, a blood test would have determined whether Claudius suffered lead poisoning. Diagnosing bipolar disorder and/or alcoholism is much more difficult. Differentiating these disorders from each other and from other psychiatric disorders is challenging, as no laboratory tests confirm the diagnosis. Ongoing clinical observation of the illness and response to medication are crucial.

In some cases, having the patient list his or her depressive and manic episodes on a “life chart” might clarify the diagnosis. This exercise can also help the patient recognize bipolar symptoms and accept that he or she has the illness, which is critical to ensuring treatment adherence. Also start medication at this time.

Treatment

Treat bipolar disorder and alcoholism simultaneously, as either disorder could worsen the other’s course.^11,12

Lithium or valproate would be probable first-line treatments for Claudius. Discuss the medication’s risks and benefits with the patient and involved family members/caretakers. Inform them that you might have to change or add medication if the patient does not respond or experiences side effects.

Psychotherapy and/or psychoeducation are integral to treating comorbid bipolar disorder and alcoholism. Claudius also could have benefited from:

• education about healthy dieting
  
• counseling against high-risk behaviors associated with alcoholism, such as domestic violence and gambling
  
• a support group for patients with bipolar disorder or a 12-step program.
  

What claudius can teach us

Although Claudius’ symptoms cannot be diagnosed with certainty, the information and perspective available today offer insight into his likely psychiatric problems. His case reminds us that:

• Patients often have multiple diagnoses. Bipolar disorder is strongly associated with substance abuse disorder—particularly alcoholism.
  
• Lead-containing alcoholic beverages are still a public health concern. Morgan et al¹³ tested 115 samples of moonshine from nine southeastern, south central, and north central U.S. states. One-third of samples contained lead >300 μg/dL. The authors estimated that excessive consumption of 25% of the samples could lead to blood lead levels consistent with lead poisoning (≥25 μg/dL).
  

Related resources

• Schwartz BS, Stewart WF, Bolla KO, et al. Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology 2000;55:1144-50.
  
• Canfield RL, Henderson CR Jr, Cory-Slechta DA, et al. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 2003;348:1517-26.
  
• Salloum IM, Thase ME. Impact of substance abuse on the course and treatment of bipolar disorder. Bipolar Disord 2000;2:269-80.
  
• Nriagu JO. Lead and lead poisoning in antiquity. New York: John Wiley and Sons; 1983.
  

• Lithium • Eskalith, others
  
• Valproate • Depakene
  

Dr. Frankenburg reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Mrs. A, age 82, has advanced Alzheimer’s disease and has resided in a nursing home for 2 years. She does not recognize that she lives in a nursing home and waits by the door for her son to take her home. She spends her days weeping, telling visitors and staff she has been abandoned and must go home to care for her children.

Recently she has been wandering from the facility. When staff attempt to direct her away from the door, she resists, becomes physically aggressive, and hollers loudly. Her behavior bothers visitors and other patients, who frequently complain.

Her primary care physician prescribes a trial of olanzapine, 10 mg/d, but she becomes confused and suffers a fall. Staff report that Mrs. A is sleeping poorly and losing weight.

Deciding how to manage agitation, aggression, or psychotic symptoms of dementia is dicey at best. You can try an atypical antipsychotic despite the FDA’s black-box warning (Risks of using vs. not using atypical antipsychotics. Current Psychiatry 2005;4(8):14-28.

• Carbamazepine • Carbatrol
  
• Donepezil • Aricept
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Trazodone • Desyrel
  
• Valproic acid • Depakote
  

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

Mrs. A, age 82, has advanced Alzheimer’s disease and has resided in a nursing home for 2 years. She does not recognize that she lives in a nursing home and waits by the door for her son to take her home. She spends her days weeping, telling visitors and staff she has been abandoned and must go home to care for her children.

Recently she has been wandering from the facility. When staff attempt to direct her away from the door, she resists, becomes physically aggressive, and hollers loudly. Her behavior bothers visitors and other patients, who frequently complain.

Her primary care physician prescribes a trial of olanzapine, 10 mg/d, but she becomes confused and suffers a fall. Staff report that Mrs. A is sleeping poorly and losing weight.

Deciding how to manage agitation, aggression, or psychotic symptoms of dementia is dicey at best. You can try an atypical antipsychotic despite the FDA’s black-box warning (Risks of using vs. not using atypical antipsychotics. Current Psychiatry 2005;4(8):14-28.

• Carbamazepine • Carbatrol
  
• Donepezil • Aricept
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Trazodone • Desyrel
  
• Valproic acid • Depakote
  

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

Mrs. A, age 82, has advanced Alzheimer’s disease and has resided in a nursing home for 2 years. She does not recognize that she lives in a nursing home and waits by the door for her son to take her home. She spends her days weeping, telling visitors and staff she has been abandoned and must go home to care for her children.

Recently she has been wandering from the facility. When staff attempt to direct her away from the door, she resists, becomes physically aggressive, and hollers loudly. Her behavior bothers visitors and other patients, who frequently complain.

Her primary care physician prescribes a trial of olanzapine, 10 mg/d, but she becomes confused and suffers a fall. Staff report that Mrs. A is sleeping poorly and losing weight.

Deciding how to manage agitation, aggression, or psychotic symptoms of dementia is dicey at best. You can try an atypical antipsychotic despite the FDA’s black-box warning (Risks of using vs. not using atypical antipsychotics. Current Psychiatry 2005;4(8):14-28.

• Carbamazepine • Carbatrol
  
• Donepezil • Aricept
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Trazodone • Desyrel
  
• Valproic acid • Depakote
  

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

Choosing medications for patients with traumatic brain injury (TBI) requires caution; some drugs slow their recovery, and no standard post-TBI treatment exists.

As consulting psychiatrist on a TBI rehabilitation team, I am asked to manage enduring cognitive and emotional problems—aggression, apathy, learning disabilities, dementia—in patients with moderate to severe head injuries. This article describes how we apply available evidence to treat neurobehavioral symptoms in these patients.

Case: An iraq war casualty

The physical medicine and rehabilitation service asks for help in managing agitation, anxiety, and nightmares in Mr. N, age 20, a U.S. combat soldier. While on patrol 2 months ago in Iraq, he suffered a penetrating right frontoparietal brain injury from an improvised explosive device.

Mr. N has undergone a right temporoparietal craniectomy with debridement, ventriculostomy placement, and scalp flap closure. He has had seizures and then pancreatitis—thought to be caused by divalproex prescribed to treat the seizures. Divalproex was replaced with phenytoin at our hospital, and the pancreatitis resolved.

How serious an injury?

TBI ranges from self-limited concussion to devastating, permanent CNS impairment and life-long disability. Brain injuries from sudden impact—from assaults, falls, motor vehicle accidents, combat, or sports—can cause diffuse axonal injury and confusion or unconsciousness, even without radiographic evidence of cerebral bleeding, edema, or mass effect.

No hierarchy or nomenclature is universally accepted for TBI. The term “concussion” is generally used for milder injury and TBI for more-severe injuries.

Concussion. The American Academy of Neurology defines concussion as a trauma-induced alteration in mental status that may or may not involve loss of consciousness. Confusion and amnesia—the hallmarks of concussion—may occur immediately after the head trauma or several minutes later.¹ This definition recognizes three concussion grades:

• Grade 1: confusion lasts
• Grade 2: confusion persists >15 minutes but without LOC
  
• Grade 3: concussion with LOC. The confusional state is marked by disorientation, delayed verbal and motor responses, inattention, incoordination, emotional lability, and slurred or incoherent speech.
  

• Mild TBI: GCS 13 to 15, LOC 1,3
  
• Moderate TBI: GCS 9 to 12, LOC 30 minutes to 7 days, and PTA 24 hours to 7 days.
  
• Severe TBI: GCS ≤8, LOC, and PTA >7 days,⁴ or any focal neuroimaging abnormalities.³
  

Using Glasgow Coma Scale scores to evaluate brain injury severity

Case continued: ‘They’re hurting me’

Mr. N meets criteria for severe TBI. He is periodically agitated and aggressive and refuses to return to physical therapy, complaining that rehabilitation nurses are intentionally hurting him. He occasionally hits the staff and throws things. His medications include:

• phenytoin, 100 mg every 6 hours for seizure prophylaxis
  
• lamotrigine, 50 mg bid for seizure prophylaxis
  
• zolpidem, 5 mg as needed at bedtime for pain
  
• methadone, 10 mg/d for pain
  
• oxycodone, 5 mg every 4 hours as needed for breakthrough pain.
  

Assessing progress

For patients such as Mr. N, TBI recovery progress is measured with the Rancho Los Amigos Scale.

The original Rancho scale—developed in 1972 by staff at the Rancho Los Amigos rehabilitation hospital in Downey, CA—described eight levels of cognitive and adaptive functioning, from coma and total care through normal cognition and independence. A 1997 revised version separates the highest cognitive functioning level (VIII, purposeful, appropriate function) into three parts, expanding the scale to 10 levels (Table 2).⁵

Of course, not all TBI patients begin recovery at Rancho level I, and unfortunately not all achieve level X. Some experience dementia caused by head trauma, with persistent memory impairment and cognitive deficits in language, apraxia, agnosia, or executive function.⁶

Most patients recover as predicted by the initial injury’s severity. Others experience diffuse cerebral swelling with sudden, rapid deterioration after what appeared to be a grade 1 or grade 2 concussion. Diffuse cerebral swelling is sometimes considered a “second-impact syndrome,” but it can also occur after a single impact.⁷ A second TBI is not universally believed to cause the precipitous decline, but animal studies suggest an additive effect of rapid sequential TBI.⁸

Table 2

10-level Rancho Los Amigos Scale for assessing TBI recovery

Recovery for a patient such as Mr. N with Rancho level IV to V TBI may be complicated by marked mood lability, spontaneous aggression, psychomotor agitation, extremely short attention with marked distractibility, little to no short-term memory, and noncooperation with treatment and care. Patients may also show disorders of diminished motivation, characterized by normal consciousness but decreased goal-directed behavior and affective flattening.⁹

Case continued: Calling in reinforcements

Besides combat nightmares, Mr. N is experiencing other signs of posttraumatic stress disorder (PTSD): intrusive memories of dead comrades, anhedonia, insomnia, irritability, and hypervigilance. We recommend a trial of citalopram, 10 mg/d, but within 1 week he becomes more irritable, agitated, and aggressive, with worsening sleep. We arrange a meeting to obtain collateral information from Mr. N’s aunt, mother, and clinical psychologist. We learn that a first-degree relative had bipolar disorder, and Mr. N lived with various relatives during childhood.

As a child, Mr. N was easily angered, hyperactive, unpredictably aggressive with peers, and impulsive. He was diagnosed with “explosive disorder” at age 8. A psychiatrist prescribed methylphenidate (which helped) and paroxetine (which worsened his behavior and aggression). Based on this history, we make a presumptive diagnosis of comorbid bipolar disorder.

Treating psychopathology

Comorbidities. Adolescents and adults with pre-existing attention-deficit/hyperactivity disorder or bipolar disorder may be predisposed to carelessness or risk taking that lead to accidents and TBI. Likewise, alcoholism and substance use disorders are risk factors for head injuries. These pre-existing conditions will complicate the post-TBI course and must be treated concurrently.

Depression and PTSD may follow a head injury and complicate recovery. In fact, post-TBI symptoms—poor sleep, poor memory and concentration, and irritability—are common to both depression and PTSD.

A team approach. Regardless of its severity or recovery stage, TBI requires multidisciplinary treatment. Physical, occupational, and speech therapies are essential initially. As recovery progresses, vocational rehabilitation may need to be added. Throughout rehabilitation, supportive individual and family therapy can help patients reintegrate into the community. Psychologists, neuropsychologists, and clinical social workers are indispensable to the treatment team.

Medication precautions

Using medications to manage post-TBI syndromes is difficult and controversial. No standard regimen exists, and few clinical trials guide treatment. Small, uncontrolled studies (human and animal) suggest commonly prescribed drugs may worsen outcomes (Table 3).^10,11 For example:

• Cognitive function improved in three TBI patients after thioridazine was discontinued in two and haloperidol in one.¹²
  
• Haloperidol given to 11 patients with TBI made no difference in rehabilitation outcomes when compared with 15 patients who did not receive the antipsychotic. Those receiving haloperidol also had longer post-trauma amnesia (5 to 30 weeks), compared with the untreated group (1 to 18 weeks).¹³
  
• In animal studies of TBI, motor recovery was slowed with haloperidol but not olanzapine,^14,15 and with clonidine,¹⁶ phenytoin,¹⁷ and trazodone.¹⁸ Phenobarbitol.¹⁹ and diazepam²⁰ have been associated with delayed behavioral recovery and chronic behavior problems, respectively, in rats with TBI. How these agents might affect human patients is speculative.
  

Medications with potential to impede TBI recovery*

• Psychostimulants have improved recovery of motor function in animal trials if given before physical therapy.¹⁴
  
• Stimulants and dopaminergic agonists such as bromocriptine and amantadine might help disorders of diminished motivation.²²
  
• Dextroamphetamine and methylphenidate have improved impulsivity, memory, and concentration in a patient with TBI.²³
  

Drugs considered safe and effective
for TBI neurobehavioral symptoms

Small studies of anticonvulsants for post-TBI agitation report:

• valproic acid might improve behavioral control and decrease aggression, and it did not worsen performance on neuropsychological testing
  
• carbamazepine reduced agitation in seven TBI patients and reduced anger outbursts in 8 of 10 others
  
• gabapentin caused paradoxical effects in two TBI patients²⁵
  
• lamotrigine improved agitation in one TBI patient.²⁶
  

• propranolol, 420 to 520 mg/d
  
• pindolol, 60 mg/d
  
• metoprolol, 200 mg/d.²¹
  

Dosing atypical antipsychotics
for agitation and aggression in TBI

Depression and PTSD in TBI patients are considered indications for selective serotonin reuptake inhibitors (SSRIs). Animal data suggest that fluoxetine is safe for patients with TBI,²⁷ though no human data have been published.

For PTSD with bipolar depression, we usually prescribe lamotrigine or combine an atypical antipsychotic with an SSRI. Lithium would be second-line therapy. PTSD with bipolar mania is more difficult to treat because little evidence guides medication choices. As with depression and PTSD, we usually combine an atypical antipsychotic with an SSRI. We try to control manic and psychotic symptoms first, then add the SSRI for anxiety after the mood becomes more stable.

Cognitive impairment. A dozen published studies and case reports indicate that donepezil improves cognition in subacute and chronic TBI. For example:

• An open-label trial showed subjective improvement in cognitive functions in 8 of 10 patients given donepezil.²⁸
  
• In a double-blind, placebo-controlled, crossover trial, short-term memory and attention improved with donepezil in 18 patients with post-acute TBI, as shown by neuropsychological test scores.²⁹
  
• A retrospective case-control study showed no significant difference in cognitive outcome between controls and 18 patients prescribed donepezil but did suggest that cognition improved more rapidly when patients started donepezil earlier in recovery.³⁰
  

Case continued: Back to rehab

We replace Mr. N’s phenytoin with carbamazepine, 700 mg/d (serum level about 12 mcg/mL), discontinue citalopram, and start him on quetiapine as a mood stabilizer, titrating the dosage to 600 mg/d over 3 weeks. We select quetiapine based on experience using it as a mood stabilizer and carbamazepine for additional mood stabilization and seizure prophylaxis.

We continue methadone and oxycodone at the same dosages for pain management, with good results. We eventually switch him from zolpidem to trazodone, 50 mg as needed at bedtime. We discontinue lamotrigine because he is no longer having seizures.

Mr. N tolerates quetiapine and carbamazepine well. The nursing staff reports he is much less irritable and aggressive and his sleep has improved, but he is not oversedated. He returns to and participates in physical, occupational, and speech therapies.

Tips for using medications

Many TBI patients are unusually sensitive to or intolerant of medication side effects. Because no randomized, controlled clinical trials support using any medication in these patients, be cautious. The following recommendations can help:

• Use psychotropics with a low risk of complications.
  
• Start with low dosages and increase gradually to assess side effects and efficacy of medication trials.
  
• Give full trials and adequate dosing before you decide a medication has not improved symptoms sufficiently.
  
• Monitor closely for side effects.
  
• Seek information from family members to evaluate a medication’s effectiveness, as patients’ cognitive deficits may limit their ability to reliably report symptoms.
  

• Silver JM, McAllister TW, Yudofsky SC (eds). Textbook of traumatic brain injury. Arlington, VA: American Psychiatric Press, 2005.
  
• Traumatic Brain Injury Resource Guide. www.neuroskills.com
  

• Amantadine • Symmetrel
  
• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol
  
• Citalopram • Celexa
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Diazepam • Valium
  
• Divalproex sodium • Depakote
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin
  
• Metoprolol • Lopressor
  
• Olanzapine • Zyprexa
  
• Oxycodone • Oxycontin
  
• Paroxetine • Paxil
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Pindolol • Visken
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

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

Choosing medications for patients with traumatic brain injury (TBI) requires caution; some drugs slow their recovery, and no standard post-TBI treatment exists.

As consulting psychiatrist on a TBI rehabilitation team, I am asked to manage enduring cognitive and emotional problems—aggression, apathy, learning disabilities, dementia—in patients with moderate to severe head injuries. This article describes how we apply available evidence to treat neurobehavioral symptoms in these patients.

Case: An iraq war casualty

The physical medicine and rehabilitation service asks for help in managing agitation, anxiety, and nightmares in Mr. N, age 20, a U.S. combat soldier. While on patrol 2 months ago in Iraq, he suffered a penetrating right frontoparietal brain injury from an improvised explosive device.

Mr. N has undergone a right temporoparietal craniectomy with debridement, ventriculostomy placement, and scalp flap closure. He has had seizures and then pancreatitis—thought to be caused by divalproex prescribed to treat the seizures. Divalproex was replaced with phenytoin at our hospital, and the pancreatitis resolved.

How serious an injury?

TBI ranges from self-limited concussion to devastating, permanent CNS impairment and life-long disability. Brain injuries from sudden impact—from assaults, falls, motor vehicle accidents, combat, or sports—can cause diffuse axonal injury and confusion or unconsciousness, even without radiographic evidence of cerebral bleeding, edema, or mass effect.

No hierarchy or nomenclature is universally accepted for TBI. The term “concussion” is generally used for milder injury and TBI for more-severe injuries.

Concussion. The American Academy of Neurology defines concussion as a trauma-induced alteration in mental status that may or may not involve loss of consciousness. Confusion and amnesia—the hallmarks of concussion—may occur immediately after the head trauma or several minutes later.¹ This definition recognizes three concussion grades:

• Grade 1: confusion lasts
• Grade 2: confusion persists >15 minutes but without LOC
  
• Grade 3: concussion with LOC. The confusional state is marked by disorientation, delayed verbal and motor responses, inattention, incoordination, emotional lability, and slurred or incoherent speech.
  

• Mild TBI: GCS 13 to 15, LOC 1,3
  
• Moderate TBI: GCS 9 to 12, LOC 30 minutes to 7 days, and PTA 24 hours to 7 days.
  
• Severe TBI: GCS ≤8, LOC, and PTA >7 days,⁴ or any focal neuroimaging abnormalities.³
  

Using Glasgow Coma Scale scores to evaluate brain injury severity

Case continued: ‘They’re hurting me’

Mr. N meets criteria for severe TBI. He is periodically agitated and aggressive and refuses to return to physical therapy, complaining that rehabilitation nurses are intentionally hurting him. He occasionally hits the staff and throws things. His medications include:

• phenytoin, 100 mg every 6 hours for seizure prophylaxis
  
• lamotrigine, 50 mg bid for seizure prophylaxis
  
• zolpidem, 5 mg as needed at bedtime for pain
  
• methadone, 10 mg/d for pain
  
• oxycodone, 5 mg every 4 hours as needed for breakthrough pain.
  

Assessing progress

For patients such as Mr. N, TBI recovery progress is measured with the Rancho Los Amigos Scale.

The original Rancho scale—developed in 1972 by staff at the Rancho Los Amigos rehabilitation hospital in Downey, CA—described eight levels of cognitive and adaptive functioning, from coma and total care through normal cognition and independence. A 1997 revised version separates the highest cognitive functioning level (VIII, purposeful, appropriate function) into three parts, expanding the scale to 10 levels (Table 2).⁵

Of course, not all TBI patients begin recovery at Rancho level I, and unfortunately not all achieve level X. Some experience dementia caused by head trauma, with persistent memory impairment and cognitive deficits in language, apraxia, agnosia, or executive function.⁶

Most patients recover as predicted by the initial injury’s severity. Others experience diffuse cerebral swelling with sudden, rapid deterioration after what appeared to be a grade 1 or grade 2 concussion. Diffuse cerebral swelling is sometimes considered a “second-impact syndrome,” but it can also occur after a single impact.⁷ A second TBI is not universally believed to cause the precipitous decline, but animal studies suggest an additive effect of rapid sequential TBI.⁸

Table 2

10-level Rancho Los Amigos Scale for assessing TBI recovery

Recovery for a patient such as Mr. N with Rancho level IV to V TBI may be complicated by marked mood lability, spontaneous aggression, psychomotor agitation, extremely short attention with marked distractibility, little to no short-term memory, and noncooperation with treatment and care. Patients may also show disorders of diminished motivation, characterized by normal consciousness but decreased goal-directed behavior and affective flattening.⁹

Case continued: Calling in reinforcements

Besides combat nightmares, Mr. N is experiencing other signs of posttraumatic stress disorder (PTSD): intrusive memories of dead comrades, anhedonia, insomnia, irritability, and hypervigilance. We recommend a trial of citalopram, 10 mg/d, but within 1 week he becomes more irritable, agitated, and aggressive, with worsening sleep. We arrange a meeting to obtain collateral information from Mr. N’s aunt, mother, and clinical psychologist. We learn that a first-degree relative had bipolar disorder, and Mr. N lived with various relatives during childhood.

As a child, Mr. N was easily angered, hyperactive, unpredictably aggressive with peers, and impulsive. He was diagnosed with “explosive disorder” at age 8. A psychiatrist prescribed methylphenidate (which helped) and paroxetine (which worsened his behavior and aggression). Based on this history, we make a presumptive diagnosis of comorbid bipolar disorder.

Treating psychopathology

Comorbidities. Adolescents and adults with pre-existing attention-deficit/hyperactivity disorder or bipolar disorder may be predisposed to carelessness or risk taking that lead to accidents and TBI. Likewise, alcoholism and substance use disorders are risk factors for head injuries. These pre-existing conditions will complicate the post-TBI course and must be treated concurrently.

Depression and PTSD may follow a head injury and complicate recovery. In fact, post-TBI symptoms—poor sleep, poor memory and concentration, and irritability—are common to both depression and PTSD.

A team approach. Regardless of its severity or recovery stage, TBI requires multidisciplinary treatment. Physical, occupational, and speech therapies are essential initially. As recovery progresses, vocational rehabilitation may need to be added. Throughout rehabilitation, supportive individual and family therapy can help patients reintegrate into the community. Psychologists, neuropsychologists, and clinical social workers are indispensable to the treatment team.

Medication precautions

Using medications to manage post-TBI syndromes is difficult and controversial. No standard regimen exists, and few clinical trials guide treatment. Small, uncontrolled studies (human and animal) suggest commonly prescribed drugs may worsen outcomes (Table 3).^10,11 For example:

• Cognitive function improved in three TBI patients after thioridazine was discontinued in two and haloperidol in one.¹²
  
• Haloperidol given to 11 patients with TBI made no difference in rehabilitation outcomes when compared with 15 patients who did not receive the antipsychotic. Those receiving haloperidol also had longer post-trauma amnesia (5 to 30 weeks), compared with the untreated group (1 to 18 weeks).¹³
  
• In animal studies of TBI, motor recovery was slowed with haloperidol but not olanzapine,^14,15 and with clonidine,¹⁶ phenytoin,¹⁷ and trazodone.¹⁸ Phenobarbitol.¹⁹ and diazepam²⁰ have been associated with delayed behavioral recovery and chronic behavior problems, respectively, in rats with TBI. How these agents might affect human patients is speculative.
  

Medications with potential to impede TBI recovery*

• Psychostimulants have improved recovery of motor function in animal trials if given before physical therapy.¹⁴
  
• Stimulants and dopaminergic agonists such as bromocriptine and amantadine might help disorders of diminished motivation.²²
  
• Dextroamphetamine and methylphenidate have improved impulsivity, memory, and concentration in a patient with TBI.²³
  

Drugs considered safe and effective
for TBI neurobehavioral symptoms

Small studies of anticonvulsants for post-TBI agitation report:

• valproic acid might improve behavioral control and decrease aggression, and it did not worsen performance on neuropsychological testing
  
• carbamazepine reduced agitation in seven TBI patients and reduced anger outbursts in 8 of 10 others
  
• gabapentin caused paradoxical effects in two TBI patients²⁵
  
• lamotrigine improved agitation in one TBI patient.²⁶
  

• propranolol, 420 to 520 mg/d
  
• pindolol, 60 mg/d
  
• metoprolol, 200 mg/d.²¹
  

Dosing atypical antipsychotics
for agitation and aggression in TBI

Depression and PTSD in TBI patients are considered indications for selective serotonin reuptake inhibitors (SSRIs). Animal data suggest that fluoxetine is safe for patients with TBI,²⁷ though no human data have been published.

For PTSD with bipolar depression, we usually prescribe lamotrigine or combine an atypical antipsychotic with an SSRI. Lithium would be second-line therapy. PTSD with bipolar mania is more difficult to treat because little evidence guides medication choices. As with depression and PTSD, we usually combine an atypical antipsychotic with an SSRI. We try to control manic and psychotic symptoms first, then add the SSRI for anxiety after the mood becomes more stable.

Cognitive impairment. A dozen published studies and case reports indicate that donepezil improves cognition in subacute and chronic TBI. For example:

• An open-label trial showed subjective improvement in cognitive functions in 8 of 10 patients given donepezil.²⁸
  
• In a double-blind, placebo-controlled, crossover trial, short-term memory and attention improved with donepezil in 18 patients with post-acute TBI, as shown by neuropsychological test scores.²⁹
  
• A retrospective case-control study showed no significant difference in cognitive outcome between controls and 18 patients prescribed donepezil but did suggest that cognition improved more rapidly when patients started donepezil earlier in recovery.³⁰
  

Case continued: Back to rehab

We replace Mr. N’s phenytoin with carbamazepine, 700 mg/d (serum level about 12 mcg/mL), discontinue citalopram, and start him on quetiapine as a mood stabilizer, titrating the dosage to 600 mg/d over 3 weeks. We select quetiapine based on experience using it as a mood stabilizer and carbamazepine for additional mood stabilization and seizure prophylaxis.

We continue methadone and oxycodone at the same dosages for pain management, with good results. We eventually switch him from zolpidem to trazodone, 50 mg as needed at bedtime. We discontinue lamotrigine because he is no longer having seizures.

Mr. N tolerates quetiapine and carbamazepine well. The nursing staff reports he is much less irritable and aggressive and his sleep has improved, but he is not oversedated. He returns to and participates in physical, occupational, and speech therapies.

Tips for using medications

Many TBI patients are unusually sensitive to or intolerant of medication side effects. Because no randomized, controlled clinical trials support using any medication in these patients, be cautious. The following recommendations can help:

• Use psychotropics with a low risk of complications.
  
• Start with low dosages and increase gradually to assess side effects and efficacy of medication trials.
  
• Give full trials and adequate dosing before you decide a medication has not improved symptoms sufficiently.
  
• Monitor closely for side effects.
  
• Seek information from family members to evaluate a medication’s effectiveness, as patients’ cognitive deficits may limit their ability to reliably report symptoms.
  

• Silver JM, McAllister TW, Yudofsky SC (eds). Textbook of traumatic brain injury. Arlington, VA: American Psychiatric Press, 2005.
  
• Traumatic Brain Injury Resource Guide. www.neuroskills.com
  

• Amantadine • Symmetrel
  
• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol
  
• Citalopram • Celexa
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Diazepam • Valium
  
• Divalproex sodium • Depakote
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin
  
• Metoprolol • Lopressor
  
• Olanzapine • Zyprexa
  
• Oxycodone • Oxycontin
  
• Paroxetine • Paxil
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Pindolol • Visken
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

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

Choosing medications for patients with traumatic brain injury (TBI) requires caution; some drugs slow their recovery, and no standard post-TBI treatment exists.

As consulting psychiatrist on a TBI rehabilitation team, I am asked to manage enduring cognitive and emotional problems—aggression, apathy, learning disabilities, dementia—in patients with moderate to severe head injuries. This article describes how we apply available evidence to treat neurobehavioral symptoms in these patients.

Case: An iraq war casualty

The physical medicine and rehabilitation service asks for help in managing agitation, anxiety, and nightmares in Mr. N, age 20, a U.S. combat soldier. While on patrol 2 months ago in Iraq, he suffered a penetrating right frontoparietal brain injury from an improvised explosive device.

Mr. N has undergone a right temporoparietal craniectomy with debridement, ventriculostomy placement, and scalp flap closure. He has had seizures and then pancreatitis—thought to be caused by divalproex prescribed to treat the seizures. Divalproex was replaced with phenytoin at our hospital, and the pancreatitis resolved.

How serious an injury?

TBI ranges from self-limited concussion to devastating, permanent CNS impairment and life-long disability. Brain injuries from sudden impact—from assaults, falls, motor vehicle accidents, combat, or sports—can cause diffuse axonal injury and confusion or unconsciousness, even without radiographic evidence of cerebral bleeding, edema, or mass effect.

No hierarchy or nomenclature is universally accepted for TBI. The term “concussion” is generally used for milder injury and TBI for more-severe injuries.

Concussion. The American Academy of Neurology defines concussion as a trauma-induced alteration in mental status that may or may not involve loss of consciousness. Confusion and amnesia—the hallmarks of concussion—may occur immediately after the head trauma or several minutes later.¹ This definition recognizes three concussion grades:

• Grade 1: confusion lasts
• Grade 2: confusion persists >15 minutes but without LOC
  
• Grade 3: concussion with LOC. The confusional state is marked by disorientation, delayed verbal and motor responses, inattention, incoordination, emotional lability, and slurred or incoherent speech.
  

• Mild TBI: GCS 13 to 15, LOC 1,3
  
• Moderate TBI: GCS 9 to 12, LOC 30 minutes to 7 days, and PTA 24 hours to 7 days.
  
• Severe TBI: GCS ≤8, LOC, and PTA >7 days,⁴ or any focal neuroimaging abnormalities.³
  

Using Glasgow Coma Scale scores to evaluate brain injury severity

Case continued: ‘They’re hurting me’

Mr. N meets criteria for severe TBI. He is periodically agitated and aggressive and refuses to return to physical therapy, complaining that rehabilitation nurses are intentionally hurting him. He occasionally hits the staff and throws things. His medications include:

• phenytoin, 100 mg every 6 hours for seizure prophylaxis
  
• lamotrigine, 50 mg bid for seizure prophylaxis
  
• zolpidem, 5 mg as needed at bedtime for pain
  
• methadone, 10 mg/d for pain
  
• oxycodone, 5 mg every 4 hours as needed for breakthrough pain.
  

Assessing progress

For patients such as Mr. N, TBI recovery progress is measured with the Rancho Los Amigos Scale.

The original Rancho scale—developed in 1972 by staff at the Rancho Los Amigos rehabilitation hospital in Downey, CA—described eight levels of cognitive and adaptive functioning, from coma and total care through normal cognition and independence. A 1997 revised version separates the highest cognitive functioning level (VIII, purposeful, appropriate function) into three parts, expanding the scale to 10 levels (Table 2).⁵

Of course, not all TBI patients begin recovery at Rancho level I, and unfortunately not all achieve level X. Some experience dementia caused by head trauma, with persistent memory impairment and cognitive deficits in language, apraxia, agnosia, or executive function.⁶

Most patients recover as predicted by the initial injury’s severity. Others experience diffuse cerebral swelling with sudden, rapid deterioration after what appeared to be a grade 1 or grade 2 concussion. Diffuse cerebral swelling is sometimes considered a “second-impact syndrome,” but it can also occur after a single impact.⁷ A second TBI is not universally believed to cause the precipitous decline, but animal studies suggest an additive effect of rapid sequential TBI.⁸

Table 2

10-level Rancho Los Amigos Scale for assessing TBI recovery

Recovery for a patient such as Mr. N with Rancho level IV to V TBI may be complicated by marked mood lability, spontaneous aggression, psychomotor agitation, extremely short attention with marked distractibility, little to no short-term memory, and noncooperation with treatment and care. Patients may also show disorders of diminished motivation, characterized by normal consciousness but decreased goal-directed behavior and affective flattening.⁹

Case continued: Calling in reinforcements

Besides combat nightmares, Mr. N is experiencing other signs of posttraumatic stress disorder (PTSD): intrusive memories of dead comrades, anhedonia, insomnia, irritability, and hypervigilance. We recommend a trial of citalopram, 10 mg/d, but within 1 week he becomes more irritable, agitated, and aggressive, with worsening sleep. We arrange a meeting to obtain collateral information from Mr. N’s aunt, mother, and clinical psychologist. We learn that a first-degree relative had bipolar disorder, and Mr. N lived with various relatives during childhood.

As a child, Mr. N was easily angered, hyperactive, unpredictably aggressive with peers, and impulsive. He was diagnosed with “explosive disorder” at age 8. A psychiatrist prescribed methylphenidate (which helped) and paroxetine (which worsened his behavior and aggression). Based on this history, we make a presumptive diagnosis of comorbid bipolar disorder.

Treating psychopathology

Comorbidities. Adolescents and adults with pre-existing attention-deficit/hyperactivity disorder or bipolar disorder may be predisposed to carelessness or risk taking that lead to accidents and TBI. Likewise, alcoholism and substance use disorders are risk factors for head injuries. These pre-existing conditions will complicate the post-TBI course and must be treated concurrently.

Depression and PTSD may follow a head injury and complicate recovery. In fact, post-TBI symptoms—poor sleep, poor memory and concentration, and irritability—are common to both depression and PTSD.

A team approach. Regardless of its severity or recovery stage, TBI requires multidisciplinary treatment. Physical, occupational, and speech therapies are essential initially. As recovery progresses, vocational rehabilitation may need to be added. Throughout rehabilitation, supportive individual and family therapy can help patients reintegrate into the community. Psychologists, neuropsychologists, and clinical social workers are indispensable to the treatment team.

Medication precautions

Using medications to manage post-TBI syndromes is difficult and controversial. No standard regimen exists, and few clinical trials guide treatment. Small, uncontrolled studies (human and animal) suggest commonly prescribed drugs may worsen outcomes (Table 3).^10,11 For example:

• Cognitive function improved in three TBI patients after thioridazine was discontinued in two and haloperidol in one.¹²
  
• Haloperidol given to 11 patients with TBI made no difference in rehabilitation outcomes when compared with 15 patients who did not receive the antipsychotic. Those receiving haloperidol also had longer post-trauma amnesia (5 to 30 weeks), compared with the untreated group (1 to 18 weeks).¹³
  
• In animal studies of TBI, motor recovery was slowed with haloperidol but not olanzapine,^14,15 and with clonidine,¹⁶ phenytoin,¹⁷ and trazodone.¹⁸ Phenobarbitol.¹⁹ and diazepam²⁰ have been associated with delayed behavioral recovery and chronic behavior problems, respectively, in rats with TBI. How these agents might affect human patients is speculative.
  

Medications with potential to impede TBI recovery*

• Psychostimulants have improved recovery of motor function in animal trials if given before physical therapy.¹⁴
  
• Stimulants and dopaminergic agonists such as bromocriptine and amantadine might help disorders of diminished motivation.²²
  
• Dextroamphetamine and methylphenidate have improved impulsivity, memory, and concentration in a patient with TBI.²³
  

Drugs considered safe and effective
for TBI neurobehavioral symptoms

Small studies of anticonvulsants for post-TBI agitation report:

• valproic acid might improve behavioral control and decrease aggression, and it did not worsen performance on neuropsychological testing
  
• carbamazepine reduced agitation in seven TBI patients and reduced anger outbursts in 8 of 10 others
  
• gabapentin caused paradoxical effects in two TBI patients²⁵
  
• lamotrigine improved agitation in one TBI patient.²⁶
  

• propranolol, 420 to 520 mg/d
  
• pindolol, 60 mg/d
  
• metoprolol, 200 mg/d.²¹
  

Dosing atypical antipsychotics
for agitation and aggression in TBI

Depression and PTSD in TBI patients are considered indications for selective serotonin reuptake inhibitors (SSRIs). Animal data suggest that fluoxetine is safe for patients with TBI,²⁷ though no human data have been published.

For PTSD with bipolar depression, we usually prescribe lamotrigine or combine an atypical antipsychotic with an SSRI. Lithium would be second-line therapy. PTSD with bipolar mania is more difficult to treat because little evidence guides medication choices. As with depression and PTSD, we usually combine an atypical antipsychotic with an SSRI. We try to control manic and psychotic symptoms first, then add the SSRI for anxiety after the mood becomes more stable.

Cognitive impairment. A dozen published studies and case reports indicate that donepezil improves cognition in subacute and chronic TBI. For example:

• An open-label trial showed subjective improvement in cognitive functions in 8 of 10 patients given donepezil.²⁸
  
• In a double-blind, placebo-controlled, crossover trial, short-term memory and attention improved with donepezil in 18 patients with post-acute TBI, as shown by neuropsychological test scores.²⁹
  
• A retrospective case-control study showed no significant difference in cognitive outcome between controls and 18 patients prescribed donepezil but did suggest that cognition improved more rapidly when patients started donepezil earlier in recovery.³⁰
  

Case continued: Back to rehab

We replace Mr. N’s phenytoin with carbamazepine, 700 mg/d (serum level about 12 mcg/mL), discontinue citalopram, and start him on quetiapine as a mood stabilizer, titrating the dosage to 600 mg/d over 3 weeks. We select quetiapine based on experience using it as a mood stabilizer and carbamazepine for additional mood stabilization and seizure prophylaxis.

We continue methadone and oxycodone at the same dosages for pain management, with good results. We eventually switch him from zolpidem to trazodone, 50 mg as needed at bedtime. We discontinue lamotrigine because he is no longer having seizures.

Mr. N tolerates quetiapine and carbamazepine well. The nursing staff reports he is much less irritable and aggressive and his sleep has improved, but he is not oversedated. He returns to and participates in physical, occupational, and speech therapies.

Tips for using medications

Many TBI patients are unusually sensitive to or intolerant of medication side effects. Because no randomized, controlled clinical trials support using any medication in these patients, be cautious. The following recommendations can help:

• Use psychotropics with a low risk of complications.
  
• Start with low dosages and increase gradually to assess side effects and efficacy of medication trials.
  
• Give full trials and adequate dosing before you decide a medication has not improved symptoms sufficiently.
  
• Monitor closely for side effects.
  
• Seek information from family members to evaluate a medication’s effectiveness, as patients’ cognitive deficits may limit their ability to reliably report symptoms.
  

• Silver JM, McAllister TW, Yudofsky SC (eds). Textbook of traumatic brain injury. Arlington, VA: American Psychiatric Press, 2005.
  
• Traumatic Brain Injury Resource Guide. www.neuroskills.com
  

• Amantadine • Symmetrel
  
• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol
  
• Citalopram • Celexa
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Diazepam • Valium
  
• Divalproex sodium • Depakote
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin
  
• Metoprolol • Lopressor
  
• Olanzapine • Zyprexa
  
• Oxycodone • Oxycontin
  
• Paroxetine • Paxil
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Pindolol • Visken
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

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

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Technology companies are offering two new computerized tools to reduce the “trial and error” of prescribing. Thanks to quantitative EEG (QEEG) testing and pharmacogenetic testing, you may one day be able to consistently choose medications that offer optimal benefit and minimal adverse events—without subjecting patients to unsuccessful trials.

How quantitative eeg works

QEEG adds modern computer and statistical analyses to traditional EEG recordings. The computer creates a graphic display on a schematic map of the head. The procedure is often called brain electrical activity mapping (BEAM) or simply “mapping.”¹

QEEG is nearly identical to EEG, but approximately 50% more electrodes are applied to the scalp. The additional electrodes provide better definition and about twice the data compared with traditional EEG.

The UCLA Quantitative EEG Laboratory developed cordance,² a QEEG measure, to study regional brain activity. Cordance is calculated with reference to absolute and relative power measures from the various electrodes on the brain. It is more closely correlated than traditional EEG with regional cerebral perfusion, which may offer clues to brain activity under different conditions such as depression and medication treatment.

What the data show

Several studies suggest that QEEG can trace response to medication.

Cook et al³ used QEEG in a double-blind study comparing response to fluoxetine, 20 mg/d, and placebo across 8 weeks in 24 adults with unipolar major depression. Subjects were classified as concordant or discordant depending on how many electrodes showed discordance.

Concordant patients showed a more-robust response to fluoxetine than did the discordant group, as evidenced by lower Beck Depression Inventory and Hamilton Rating Scale for Depression (HRSD) scores. The findings suggest that cordance may identify patients who will or will not respond to an antidepressant.

Cook et al⁴ also used cordance to measure response to fluoxetine, 20 mg/d, venlafaxine, 150 mg/d, or placebo in 51 adults with unipolar depression. Responders to antidepressants (defined as HRSD score ≤10) showed decreased prefrontal cordance after 48 hours and 1 week, suggesting that the prefrontal region may mediate antidepressant response.

A recent study in Korea⁵ investigated the effects of methylphenidate, 0.7 mg/kg/d (range 15 to 35 mg/d) on QEEG patterns in 20 boys ages 6 to 12 while at work or rest. Numerous changes in band waves were seen during continuous performance tests, but none were reported while the subjects were at rest. This suggests that methylphenidate exerts greater electrophysiologic influence during attention-related tasks.

Clinical applicability

QEEG has just begun to enter mainstream practice, with vendors offering analysis services. As patients increasingly demand improved diagnostic reliability and medication effectiveness, QEEG use could become a standard of practice within 5 years.

Lexicor offers a QEEG analysis to diagnose attention-deficit/hyperactivity disorder based on theta/beta band wave ratio. Lexicor says its analysis offers 86% to 90% sensitivity and 94% to 98% specificity, both far greater than traditional methods such as the Child Behavior Checklist, Behavior Assessment System for Children, and Devereaux Scales of Mental Disorder.

Major health plans offer limited coverage of quantitative EEG testing, however, so many patients would pay $200 or more for tests out of pocket. Also, the American Academy of Neurology and American Clinical Neurophysiology Society endorse QEEG for use in screening for and assessing epilepsy, but not in mental disorders,⁶ making insurers less likely to cover these tests for psychiatric purposes.

Pharmacogenetic testing

With the sequencing of the human genome and improved speed of genetic analysis, pharmacogenetic testing could supplement quantitative EEG in identifying an appropriate medication.

Companies such as Genelex (www.healthanddna.com/professional/pharmacogenetics.html) and Signature Genetics (www.signaturegenetics.com) have begun offering tests to detect variants of the cytochrome-P(CYP) 2C9, 2C19, 2D6, and 1A2 genes. The findings indicate if the patient will metabolize a medication too slowly or rapidly through these pathways. Psychiatrists can then adjust the dosage accordingly or try another medication. Physicians can order any combination of gene tests, which cost about $150 to $200 each, or all available tests for a discounted price of approximately $600.

Genelex and Signature Genetics can create individualized CYP-450 function reports to facilitate prescribing and customized reports that take into account the patient’s medication and diet regimen. Genelex also offers an Internet-based software tool, GeneMedRx, which allows doctors to customize medication regimens based on potential drug-drug interactions and genomic information.

Signature Genetics offers a prospective assessment of drugs based on genetic test results. This assessment provides a comprehensive report of which medications are affected by the test results.

Genetic profiling can help psychiatrists improve the likelihood of treatment success and minimize potential drug-drug interactions and adverse reactions. Patients will be more satisfied, knowing that their medications fit their individual needs. Also, as more is learned about genetic analysis, genetic testing could one day reveal susceptibility to Alzheimer’s disease, heart attack risk, or other medical problems.

As with QEEG, however, few insurance companies cover genetic testing. Also, insurance companies might charge higher premiums to patients found to have a higher likelihood of developing certain diseases.

Related resources

• Indiana University School of Medicine. Drug interactions table. http://medicine.iupui.edu/flockhart/clinlist.htm.

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

Technology companies are offering two new computerized tools to reduce the “trial and error” of prescribing. Thanks to quantitative EEG (QEEG) testing and pharmacogenetic testing, you may one day be able to consistently choose medications that offer optimal benefit and minimal adverse events—without subjecting patients to unsuccessful trials.

How quantitative eeg works

QEEG adds modern computer and statistical analyses to traditional EEG recordings. The computer creates a graphic display on a schematic map of the head. The procedure is often called brain electrical activity mapping (BEAM) or simply “mapping.”¹

QEEG is nearly identical to EEG, but approximately 50% more electrodes are applied to the scalp. The additional electrodes provide better definition and about twice the data compared with traditional EEG.

The UCLA Quantitative EEG Laboratory developed cordance,² a QEEG measure, to study regional brain activity. Cordance is calculated with reference to absolute and relative power measures from the various electrodes on the brain. It is more closely correlated than traditional EEG with regional cerebral perfusion, which may offer clues to brain activity under different conditions such as depression and medication treatment.

What the data show

Several studies suggest that QEEG can trace response to medication.

Cook et al³ used QEEG in a double-blind study comparing response to fluoxetine, 20 mg/d, and placebo across 8 weeks in 24 adults with unipolar major depression. Subjects were classified as concordant or discordant depending on how many electrodes showed discordance.

Concordant patients showed a more-robust response to fluoxetine than did the discordant group, as evidenced by lower Beck Depression Inventory and Hamilton Rating Scale for Depression (HRSD) scores. The findings suggest that cordance may identify patients who will or will not respond to an antidepressant.

Cook et al⁴ also used cordance to measure response to fluoxetine, 20 mg/d, venlafaxine, 150 mg/d, or placebo in 51 adults with unipolar depression. Responders to antidepressants (defined as HRSD score ≤10) showed decreased prefrontal cordance after 48 hours and 1 week, suggesting that the prefrontal region may mediate antidepressant response.

A recent study in Korea⁵ investigated the effects of methylphenidate, 0.7 mg/kg/d (range 15 to 35 mg/d) on QEEG patterns in 20 boys ages 6 to 12 while at work or rest. Numerous changes in band waves were seen during continuous performance tests, but none were reported while the subjects were at rest. This suggests that methylphenidate exerts greater electrophysiologic influence during attention-related tasks.

Clinical applicability