Evidence-Based Reviews

Mr. P, age 41, has a “problem with anger.” Since age 17, he has had sudden outbursts of screaming and shouting, with occasional minor damage to objects. These outbursts—including episodes of “road rage”—occur once or more per week and almost daily for months at a time.

Mr. P has also had more violent episodes— sometimes every 2 to 3 months—in which he has punched holes in walls, destroyed a computer with a hammer, and assaulted other people with his fists. These events are not premeditated and are typically triggered by Mr. P’s frustration at not being “perfect” or by others breaking what he considers “general rules of conduct.”

The day before his initial visit, while he was stuck in traffic, Mr. P saw a car speeding down the shoulder. Enraged, he pulled in front of the car so that the driver had to slam on the brakes. He jumped out of his car and approached the other driver, shouting obscenities. The other driver locked her door and tried to ignore Mr. P until he returned to his car. Mr. P noted that this episode “ruined” his day because of his lingering anger and irritability.

Intermittent explosive disorder (IED) is more common and complex than was once thought, based on recent evidence. Recurrent, problematic, impulsive aggression is highly comorbid with other psychiatric conditions—including mood and personality disorders—and undermines social relationships and job performance. Typical characteristics of IED are outlined in Table 1.^1-3

Table 1

Typical characteristics of intermittent explosive disorder

Onset in childhood or adolescence (mean age 15), with average duration ±20 years
Aggressive outbursts:
rapid onset, often without a recognizable prodrome short-lived (<30 minutes) verbal assault, destructive and nondestructive property assault, or physical assault usually in response to minor provocation by close intimate or associate
Some episodes may appear without identifiable provocation
Male to female ratio 3:1, although some data suggest gender parity
Source: Adapted from references 1-3

This article offers updated diagnostic criteria and a two-pronged algorithm that can help you diagnose and treat this aggression disorder.

HOW COMMON IS IED?

DSM-IV states that IED is “apparently rare.” This statement is far from surprising, given the limitations of DSM criteria. Surveys of hospitalized patients in the 1980s found that only 1.1% met DSM-III criteria for IED.⁴ In another study of more than 400 patients seeking treatment for aggression, only 1.8% met DSM-III criteria for IED (although far more would likely have met DSM-IV criteria).⁵

A more recent survey of 411 psychiatric outpatients⁶ found that 3.8% met current and 6.2% met lifetime DSM-IV criteria for IED, using the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Reanalysis of a threefold larger data set from the same study site (Coccaro and Zimmerman, unpublished) yielded the same result.

Far from rare. More recently, our findings from a small sample suggested that the community rate of lifetime IED is about 4% by DSM-IV criteria and 5% by research criteria. In the United States, we estimate that the lifetime rate of IED could be 4.5 to 18 million persons using DSM-IV criteria or 6.7 to 22.2 million using IED research criteria. If so, IED is at least as common as other major psychiatric disorders, including schizophrenia or bipolar illness. The ongoing National Comorbidity Study is expected to produce more definitive community data.

PSYCHIATRIC COMORBIDITY

Axis I disorders. IED is highly comorbid with mood, anxiety, and substance use disorders,^3,7,8 although no causal relationship has been shown

Mood and substance abuse disorders. IED’s age of onset may precede that of mood and substance use disorders, according to analysis of our unpublished data. If so, comorbid IED may not occur in the context of mood or substance use disorders.

Anxiety disorders. We have noted a similar pattern with IED and anxiety disorders, although phobic anxiety disorders (simple or social phobia) tend to manifest earlier than IED. This suggests that early-onset phobic anxiety might be associated with an increased risk of IED in adolescence or young adulthood.

Bipolar disorder. McElroy⁹ has suggested a relationship between IED and bipolar disorder. In some samples, as many as one-half of IED patients (56%) have comorbid bipolar disorder when one includes bipolar II and cyclothymia.³ Moreover, some subjects’ aggressive episodes appear to resemble “microdysphoric manic episodes.”⁹ Other studies,⁸ however, find a much lower rate (10% or less) of IED comorbidity with bipolar illness.

Bipolar disorder overall may not be highly comorbid with IED, although rates may be higher in specialty clinic samples. In individuals with any kind of bipolar disorder, mood stabilizers— rather than selective serotonin reuptake inhibitors (SSRIs)—are probably the better choice as first-line treatment of IED.⁹

 

Axis II disorders. DSM-IV allows IED diagnosis in individuals with borderline or antisocial personality disorder, as long as these cluster B disorders do not better explain the aggressive behavior. How a clinician makes this distinction is not clear; in fact, most clinicians do not diagnose IED in patients with personality disorders, regardless of the clinical picture.

IED comorbidity with borderline or antisocial personality disorders varies with the sample. Persons with personality disorders who seek treatment of aggressive behavior are more likely to have comorbid IED (90%) than those not seeking treatment who are outpatients (50%) or in the community (25%).^1,7

Individuals with personality disorders and IED score higher in aggression and lower in psychosocial function than do similar individuals without IED,⁷ indicating that the additional diagnosis is relevant.

Case report continued.

Mr. P’s outbursts have cost him several friendships, including romantic relationships. He has never advanced at work because he is seen as too volatile to supervise subordinates. Though some of Mr. P’s aggressive outbursts have occurred under the influence of alcohol, most are not related to alcohol or drug use. He has no medical problems and no other psychiatric history.

A full diagnostic evaluation uncovers a personality disorder, not otherwise specified (eight scattered traits from obsessive-compulsive personality disorder and from each of the cluster B personality disorders), and no Axis I condition other than intermittent explosive disorder.

PROBLEMS DEFINING IED

Intermittent explosive disorder is the only DSM diagnosis that applies to persons with histories of recurrent, problematic aggression not caused by another mental or physical disorder. Even so, little research on IED is available. DSM criteria for IED are poorly operationalized and have improved only modestly since the diagnosis was first included in DSM-III. In that revision, IED had four criteria.

“A” criteria specified recurrent outbursts of “seriously assaultive or destructive behavior,” but left unanswered important questions such as:

• What behavior crosses the threshold for seriously” assaultive or destructive?
• Does any physical assault qualify, or only those that cause physical injury (or stigmata)?
• How often or within what time must the behavior occur?

The phrase “recurrent acts of aggression” suggested that at least three acts of aggression were required to reach the threshold, but DSM-III provided no guidelines.

“B” criteria stated that the aggression should be out of proportion to the provocation. But how should one judge this criterion, when provocative stimuli sometimes are clearly sufficient to prompt a justifiably aggressive act?

“C” criteria excluded persons who are aggressive or impulsive between ill-defined “aggressive episodes.” This exclusion was especially limiting because individuals with recurrent, problematic, aggressive behaviors generally are impulsive and aggressive between more-severe outbursts. Excluding those who otherwise met diagnostic criteria for IED led to a spuriously low prevalence rate and limited the number of research subjects. DSM-IV eliminated this criterion but made no other notable changes in IED criteria.

“D” criteria in DSM-III and III-R further restricted the number of individuals who could meet this diagnosis:

• In DSM-III, antisocial personality disorder excluded the diagnosis of IED.
• In DSM-III-R, borderline personality disorder was added as an exclusionary factor.

Because of these restrictions, very few clinically valid cases of IED (individuals meeting A and B criteria) could receive an IED diagnosis.¹⁰

EVOLVING DIAGNOSTIC CRITERIA

By the early 1990s, DSM diagnostic criteria clearly severely restricted the study of recurrent, problematic aggression, even though research since DSM-III had greatly advanced our understanding of human aggression. For example, data linked impulsive aggression to deficits in central serotonergic function and suggested that agents that enhance serotonergic activity could modify this behavior.

Some investigators proposed research criteria for IED (IED-R) so that individuals with recurrent, problematic, impulsive aggression could be identified and studied. Research criteria first published in 1998⁷ proposed six changes/clarifications in IED diagnostic criteria:

Lower-intensity aggression. The scope of aggressive behavior was expanded to include verbal and indirect physical aggression, provided that these behaviors are associated with distress and/or impairment. Data from double-blind, placebo-controlled trials indicated that these lower-intensity (although usually higher frequency) behaviors respond well to treatment with SSRIs.^11,12

Impulsivity. The aggression was specified as impulsive. This change identified individuals with greater liability for deficits in central serotonergic function and excluded individuals with premeditated or criminal aggression.

A minimal frequency of aggression over time was proposed to make the IED diagnosis more reliable and to ensure that persons with only occasional impulsive aggressive outbursts (especially of low severity) were given this diagnosis.

Subjective distress (in the individual) and/or social or occupational dysfunction was proposed so that putatively aggressive individuals are not diagnosed for manifesting behaviors that are not functionally severe.

 

Diagnostic exclusionary criteria were modified so that individuals with:

• antisocial or borderline personality disorder could be diagnosed with IED if otherwise warranted
• aggressive behaviors confined within major depression episodes could not be diagnosed with IED.

This last change recognized that impulsive, aggressive outbursts could point to major depressive disorder.

When the revised criteria were tested in patients seeking treatment for aggression, those who met IED-R criteria were found to exhibit significantly greater aggression and impulsivity (using validated scales) and lower global functioning than those who did not.⁷ Statistical adjustments made to account for aggression score differences eliminated the difference in global functioning, which suggested a direct link between aggression and global function in individuals with IED-R.

Two patterns. Later research uncovered at least patterns of aggressive outbursts:

• low intensity at high frequency (such as verbal arguments or door slamming approximately twice weekly)
• high intensity at low frequency (such as physical aggression resulting in injury or destruction of nontrivial property at least three times per year).

Data revealed that 69% of individuals with IED-like histories displayed both aggression patterns, 20% displayed only the high-intensity/low-frequency pattern, and 11% displayed only the low-intensity/high-frequency pattern.

Because further analysis revealed no important differences between these groups in measures of aggression and impulsivity, IED-R criteria were revised to include both patterns in the “A” criteria. This revision integrated the essences of IED-R and DSM criteria into one diagnostic set (Table 2).

INFLUENCE OF HEREDITY

No twin or adoption studies of IED have been performed. However, family history data suggest that IED (or IED-type behavior) is familial. I recently conducted a blinded, controlled, family history study using IED-R criteria and found a significantly elevated risk for IED (p < 0.01) in relatives of persons with a history of IED (26%), compared with non-IED controls (8%). Comorbid conditions did not affect the risk among the IED subjects or their relatives, suggesting that IED is familial and independent of other conditions.¹³

Nearly all studies of aggression’s biology and treatment have measured aggression as a dimensional variable along a continuous scale from low to high.¹⁴ Our studies have allowed us to explore biological and treatment response correlates. In preliminary analyses, we have found that the maximal prolactin response to d-fenfluramine challenge and the number of platelet serotonin transporter binding sites are:

• reduced in subjects meeting research criteria for IED
• inversely correlated with dimensional measures of impulsive aggression.

Table 2

Updated diagnostic criteria for intermittent explosive disorder

A. Recurrent incidents of aggression manifest as either:
1. Verbal or physical aggression towards other people, animals, or property occurring twice weekly on average for 1 month
OR
2. Three episodes involving physical assault against other people or destruction of property over a 1-year period
B. The degree of aggressiveness expressed is grossly out of proportion to the provocation or any precipitating psychosocial stressors
C. The aggressive behavior is generally not premeditated (ie, is impulsive) and is not committed to achieve a tangible objective (such as money, power, intimidation, etc.)
D. The aggressive behavior causes marked distress in the individual or impairs occupational or interpersonal functioning
E. The aggressive behavior is not better explained by another mental disorder (such as a major depressive/manic/psychotic disorder, attention-deficit/hyperactivity disorder, general medical condition [head trauma, Alzheimer’s disease], or due to the direct physiologic effects of a substance)
Source: Adapted from reference 7

Earlier, Virkkunen et al¹⁵ reported reduced cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in persons diagnosed with IED based on DSM-III criteria, compared with persons who were not diagnosed with IED and those who demonstrated nonimpulsive aggression.

TREATING IED

Cognitive therapy. Few double-blind, randomized, placebo-controlled trials of any treatments for IED have been published. Trials using cognitive-behavioral approaches have reduced self-rated anger and its expression in young adults with anger disorders.¹⁶ Although many of these subjects may have had IED, it is not known if this approach works in IED.

Table 3

Characteristic behaviors of aggressive individuals*

Severity	Behaviors
Mildly aggressive	Occasional verbal arguments and/or temper tantrums
Moderately aggressive	Frequent verbal arguments and temper tantrums (about twice weekly on average), occasional destruction of property, rare or occasional physical assault against others (usually without injury)
Highly aggressive	Frequent verbal arguments and temper tantrums (about twice weekly) and/or more than occasional destruction of property or physical assault against others, sometimes with injury
* Characteristics given are descriptive and not based on data.

Drug therapy. SSRIs. A trial by this author using fluoxetine showed that impulsive aggressive behavior responds to treatment that targets the central serotonergic system.¹² Forty subjects with personality disorders and histories of impulsive aggression received fluoxetine, 20 to 60 mg qd, or placebo for 12 weeks. Fluoxetine reduced overt aggression and irritability about 67% more than placebo, as assessed by the Overt Aggression Scale Modified for Outpatients (OAS-M).

 

All subjects met research criteria for IED. A reanalysis suggests that SSRIs may be most effective in moderately aggressive patients (Table 3),¹⁷ whose serotonergic system may be less impaired than that of highly aggressive patients.¹⁸

Mood stabilizers. Impulsively aggressive subjects who do not respond to an SSRI may respond to a mood stabilizer.¹⁹ An antiaggressive response in IED-like subjects has been reported for lithium,²⁰ carbamazepine,²¹ and diphenylhydantoin.²²

Recently, Hollander et al²³ reported greater reduction in overt aggression scores in IED subjects with a DSM cluster B personality disorder who were treated with divalproex, compared with placebo. This study used the same design and outcome measure as our study¹² and included subjects who met both DSM-IV and research criteria for IED.

For unknown reasons, divalproex was no more effective than placebo in IED subjects without cluster B personality disorder. More research is needed to uncover predictors of antiaggressive response in IED subjects.

Unipolar vs. bipolar. McElroy⁹ has suggested using SSRIs (or other antidepressants) as first-line treatment for IED subjects with unipolar affective symptoms and mood stabilizers for those with bipolar affective symptoms. IED subjects without bipolar affective symptoms should be treated first with SSRIs (Algorithm). Preliminary data suggest a role for atypical antipsychotics to treat aggressive behavior in patients with schizophrenia or bipolar disorder, but no empiric data exist.

Beta blockers such as propranolol also may be considered.² However, beta blockers are more difficult to dose and are associated with more burdensome side effects, compared with SSRIs.

Algorithm Suggested 2-pronged approach for treating intermittent explosive disorder

* With or without an anger management program, which may precede drug interventionThe full effects of antiaggressive treatment with an SSRI (E. Coccaro, unpublished observations) or a mood stabilizer¹⁹ may take 3 months to observe^12,20,22,23 and tend to disappear soon after treatment is discontinued.

Therefore, an adequate trial of SSRIs or mood stabilizers is no less than 3 months. If improvement is seen, continue drug treatment indefinitely.

Case report continued.

Mr. P was started on an SSRI. His aggressive outbursts decreased in intensity and frequency over 3 months but were not eliminated. After 6 months he dropped out of treatment, but returned 5 weeks later because his aggressive outbursts had resumed their pre-treatment level.

SSRI treatment was restarted, and Mr. P began a 12-week anger management course of relaxation training, cognitive restructuring, and coping skills training. He gained greater control over his aggressive outbursts and continues monthly medication checks and anger management “booster sessions.”

Related resources

• Galovski T, Blanchard EB, Veazey C. Intermittent explosive disorder and other psychiatric comorbidity among court-referred and self-referred aggressive drivers. Behav Res Ther 2002;40:641-51.
• Olvera RL. Intermittent explosive disorder: epidemiology, diagnosis and management. CNS Drugs 2002;16:517-26.

Drug brand names

• Carbamazepine • Tegretol
• Diphenylhydantoin • Dilantin
• Divalproex • Depakote
• Fluoxetine • Prozac
• Lithium • Lithobid
• Propanolol • Inderal

Disclosure

Dr. Coccaro reports that he receives research grants and serves on the speaker’s bureau or as a consultant to Eli Lilly and Co., Abbott Laboratories, GlaxoSmithKline, and Forrest Laboratories.

Mr. P, age 41, has a “problem with anger.” Since age 17, he has had sudden outbursts of screaming and shouting, with occasional minor damage to objects. These outbursts—including episodes of “road rage”—occur once or more per week and almost daily for months at a time.

Mr. P has also had more violent episodes— sometimes every 2 to 3 months—in which he has punched holes in walls, destroyed a computer with a hammer, and assaulted other people with his fists. These events are not premeditated and are typically triggered by Mr. P’s frustration at not being “perfect” or by others breaking what he considers “general rules of conduct.”

The day before his initial visit, while he was stuck in traffic, Mr. P saw a car speeding down the shoulder. Enraged, he pulled in front of the car so that the driver had to slam on the brakes. He jumped out of his car and approached the other driver, shouting obscenities. The other driver locked her door and tried to ignore Mr. P until he returned to his car. Mr. P noted that this episode “ruined” his day because of his lingering anger and irritability.

Intermittent explosive disorder (IED) is more common and complex than was once thought, based on recent evidence. Recurrent, problematic, impulsive aggression is highly comorbid with other psychiatric conditions—including mood and personality disorders—and undermines social relationships and job performance. Typical characteristics of IED are outlined in Table 1.^1-3

Table 1

Typical characteristics of intermittent explosive disorder

Onset in childhood or adolescence (mean age 15), with average duration ±20 years
Aggressive outbursts:
rapid onset, often without a recognizable prodrome short-lived (<30 minutes) verbal assault, destructive and nondestructive property assault, or physical assault usually in response to minor provocation by close intimate or associate
Some episodes may appear without identifiable provocation
Male to female ratio 3:1, although some data suggest gender parity
Source: Adapted from references 1-3

This article offers updated diagnostic criteria and a two-pronged algorithm that can help you diagnose and treat this aggression disorder.

HOW COMMON IS IED?

DSM-IV states that IED is “apparently rare.” This statement is far from surprising, given the limitations of DSM criteria. Surveys of hospitalized patients in the 1980s found that only 1.1% met DSM-III criteria for IED.⁴ In another study of more than 400 patients seeking treatment for aggression, only 1.8% met DSM-III criteria for IED (although far more would likely have met DSM-IV criteria).⁵

A more recent survey of 411 psychiatric outpatients⁶ found that 3.8% met current and 6.2% met lifetime DSM-IV criteria for IED, using the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Reanalysis of a threefold larger data set from the same study site (Coccaro and Zimmerman, unpublished) yielded the same result.

Far from rare. More recently, our findings from a small sample suggested that the community rate of lifetime IED is about 4% by DSM-IV criteria and 5% by research criteria. In the United States, we estimate that the lifetime rate of IED could be 4.5 to 18 million persons using DSM-IV criteria or 6.7 to 22.2 million using IED research criteria. If so, IED is at least as common as other major psychiatric disorders, including schizophrenia or bipolar illness. The ongoing National Comorbidity Study is expected to produce more definitive community data.

PSYCHIATRIC COMORBIDITY

Axis I disorders. IED is highly comorbid with mood, anxiety, and substance use disorders,^3,7,8 although no causal relationship has been shown

Mood and substance abuse disorders. IED’s age of onset may precede that of mood and substance use disorders, according to analysis of our unpublished data. If so, comorbid IED may not occur in the context of mood or substance use disorders.

Anxiety disorders. We have noted a similar pattern with IED and anxiety disorders, although phobic anxiety disorders (simple or social phobia) tend to manifest earlier than IED. This suggests that early-onset phobic anxiety might be associated with an increased risk of IED in adolescence or young adulthood.

Bipolar disorder. McElroy⁹ has suggested a relationship between IED and bipolar disorder. In some samples, as many as one-half of IED patients (56%) have comorbid bipolar disorder when one includes bipolar II and cyclothymia.³ Moreover, some subjects’ aggressive episodes appear to resemble “microdysphoric manic episodes.”⁹ Other studies,⁸ however, find a much lower rate (10% or less) of IED comorbidity with bipolar illness.

Bipolar disorder overall may not be highly comorbid with IED, although rates may be higher in specialty clinic samples. In individuals with any kind of bipolar disorder, mood stabilizers— rather than selective serotonin reuptake inhibitors (SSRIs)—are probably the better choice as first-line treatment of IED.⁹

 

Axis II disorders. DSM-IV allows IED diagnosis in individuals with borderline or antisocial personality disorder, as long as these cluster B disorders do not better explain the aggressive behavior. How a clinician makes this distinction is not clear; in fact, most clinicians do not diagnose IED in patients with personality disorders, regardless of the clinical picture.

IED comorbidity with borderline or antisocial personality disorders varies with the sample. Persons with personality disorders who seek treatment of aggressive behavior are more likely to have comorbid IED (90%) than those not seeking treatment who are outpatients (50%) or in the community (25%).^1,7

Individuals with personality disorders and IED score higher in aggression and lower in psychosocial function than do similar individuals without IED,⁷ indicating that the additional diagnosis is relevant.

Case report continued.

Mr. P’s outbursts have cost him several friendships, including romantic relationships. He has never advanced at work because he is seen as too volatile to supervise subordinates. Though some of Mr. P’s aggressive outbursts have occurred under the influence of alcohol, most are not related to alcohol or drug use. He has no medical problems and no other psychiatric history.

A full diagnostic evaluation uncovers a personality disorder, not otherwise specified (eight scattered traits from obsessive-compulsive personality disorder and from each of the cluster B personality disorders), and no Axis I condition other than intermittent explosive disorder.

PROBLEMS DEFINING IED

Intermittent explosive disorder is the only DSM diagnosis that applies to persons with histories of recurrent, problematic aggression not caused by another mental or physical disorder. Even so, little research on IED is available. DSM criteria for IED are poorly operationalized and have improved only modestly since the diagnosis was first included in DSM-III. In that revision, IED had four criteria.

“A” criteria specified recurrent outbursts of “seriously assaultive or destructive behavior,” but left unanswered important questions such as:

• What behavior crosses the threshold for seriously” assaultive or destructive?
• Does any physical assault qualify, or only those that cause physical injury (or stigmata)?
• How often or within what time must the behavior occur?

The phrase “recurrent acts of aggression” suggested that at least three acts of aggression were required to reach the threshold, but DSM-III provided no guidelines.

“B” criteria stated that the aggression should be out of proportion to the provocation. But how should one judge this criterion, when provocative stimuli sometimes are clearly sufficient to prompt a justifiably aggressive act?

“C” criteria excluded persons who are aggressive or impulsive between ill-defined “aggressive episodes.” This exclusion was especially limiting because individuals with recurrent, problematic, aggressive behaviors generally are impulsive and aggressive between more-severe outbursts. Excluding those who otherwise met diagnostic criteria for IED led to a spuriously low prevalence rate and limited the number of research subjects. DSM-IV eliminated this criterion but made no other notable changes in IED criteria.

“D” criteria in DSM-III and III-R further restricted the number of individuals who could meet this diagnosis:

• In DSM-III, antisocial personality disorder excluded the diagnosis of IED.
• In DSM-III-R, borderline personality disorder was added as an exclusionary factor.

Because of these restrictions, very few clinically valid cases of IED (individuals meeting A and B criteria) could receive an IED diagnosis.¹⁰

EVOLVING DIAGNOSTIC CRITERIA

By the early 1990s, DSM diagnostic criteria clearly severely restricted the study of recurrent, problematic aggression, even though research since DSM-III had greatly advanced our understanding of human aggression. For example, data linked impulsive aggression to deficits in central serotonergic function and suggested that agents that enhance serotonergic activity could modify this behavior.

Some investigators proposed research criteria for IED (IED-R) so that individuals with recurrent, problematic, impulsive aggression could be identified and studied. Research criteria first published in 1998⁷ proposed six changes/clarifications in IED diagnostic criteria:

Lower-intensity aggression. The scope of aggressive behavior was expanded to include verbal and indirect physical aggression, provided that these behaviors are associated with distress and/or impairment. Data from double-blind, placebo-controlled trials indicated that these lower-intensity (although usually higher frequency) behaviors respond well to treatment with SSRIs.^11,12

Impulsivity. The aggression was specified as impulsive. This change identified individuals with greater liability for deficits in central serotonergic function and excluded individuals with premeditated or criminal aggression.

A minimal frequency of aggression over time was proposed to make the IED diagnosis more reliable and to ensure that persons with only occasional impulsive aggressive outbursts (especially of low severity) were given this diagnosis.

Subjective distress (in the individual) and/or social or occupational dysfunction was proposed so that putatively aggressive individuals are not diagnosed for manifesting behaviors that are not functionally severe.

 

Diagnostic exclusionary criteria were modified so that individuals with:

• antisocial or borderline personality disorder could be diagnosed with IED if otherwise warranted
• aggressive behaviors confined within major depression episodes could not be diagnosed with IED.

This last change recognized that impulsive, aggressive outbursts could point to major depressive disorder.

When the revised criteria were tested in patients seeking treatment for aggression, those who met IED-R criteria were found to exhibit significantly greater aggression and impulsivity (using validated scales) and lower global functioning than those who did not.⁷ Statistical adjustments made to account for aggression score differences eliminated the difference in global functioning, which suggested a direct link between aggression and global function in individuals with IED-R.

Two patterns. Later research uncovered at least patterns of aggressive outbursts:

• low intensity at high frequency (such as verbal arguments or door slamming approximately twice weekly)
• high intensity at low frequency (such as physical aggression resulting in injury or destruction of nontrivial property at least three times per year).

Data revealed that 69% of individuals with IED-like histories displayed both aggression patterns, 20% displayed only the high-intensity/low-frequency pattern, and 11% displayed only the low-intensity/high-frequency pattern.

Because further analysis revealed no important differences between these groups in measures of aggression and impulsivity, IED-R criteria were revised to include both patterns in the “A” criteria. This revision integrated the essences of IED-R and DSM criteria into one diagnostic set (Table 2).

INFLUENCE OF HEREDITY

No twin or adoption studies of IED have been performed. However, family history data suggest that IED (or IED-type behavior) is familial. I recently conducted a blinded, controlled, family history study using IED-R criteria and found a significantly elevated risk for IED (p < 0.01) in relatives of persons with a history of IED (26%), compared with non-IED controls (8%). Comorbid conditions did not affect the risk among the IED subjects or their relatives, suggesting that IED is familial and independent of other conditions.¹³

Nearly all studies of aggression’s biology and treatment have measured aggression as a dimensional variable along a continuous scale from low to high.¹⁴ Our studies have allowed us to explore biological and treatment response correlates. In preliminary analyses, we have found that the maximal prolactin response to d-fenfluramine challenge and the number of platelet serotonin transporter binding sites are:

• reduced in subjects meeting research criteria for IED
• inversely correlated with dimensional measures of impulsive aggression.

Table 2

Updated diagnostic criteria for intermittent explosive disorder

A. Recurrent incidents of aggression manifest as either:
1. Verbal or physical aggression towards other people, animals, or property occurring twice weekly on average for 1 month
OR
2. Three episodes involving physical assault against other people or destruction of property over a 1-year period
B. The degree of aggressiveness expressed is grossly out of proportion to the provocation or any precipitating psychosocial stressors
C. The aggressive behavior is generally not premeditated (ie, is impulsive) and is not committed to achieve a tangible objective (such as money, power, intimidation, etc.)
D. The aggressive behavior causes marked distress in the individual or impairs occupational or interpersonal functioning
E. The aggressive behavior is not better explained by another mental disorder (such as a major depressive/manic/psychotic disorder, attention-deficit/hyperactivity disorder, general medical condition [head trauma, Alzheimer’s disease], or due to the direct physiologic effects of a substance)
Source: Adapted from reference 7

Earlier, Virkkunen et al¹⁵ reported reduced cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in persons diagnosed with IED based on DSM-III criteria, compared with persons who were not diagnosed with IED and those who demonstrated nonimpulsive aggression.

TREATING IED

Cognitive therapy. Few double-blind, randomized, placebo-controlled trials of any treatments for IED have been published. Trials using cognitive-behavioral approaches have reduced self-rated anger and its expression in young adults with anger disorders.¹⁶ Although many of these subjects may have had IED, it is not known if this approach works in IED.

Table 3

Characteristic behaviors of aggressive individuals*

Severity	Behaviors
Mildly aggressive	Occasional verbal arguments and/or temper tantrums
Moderately aggressive	Frequent verbal arguments and temper tantrums (about twice weekly on average), occasional destruction of property, rare or occasional physical assault against others (usually without injury)
Highly aggressive	Frequent verbal arguments and temper tantrums (about twice weekly) and/or more than occasional destruction of property or physical assault against others, sometimes with injury
* Characteristics given are descriptive and not based on data.

Drug therapy. SSRIs. A trial by this author using fluoxetine showed that impulsive aggressive behavior responds to treatment that targets the central serotonergic system.¹² Forty subjects with personality disorders and histories of impulsive aggression received fluoxetine, 20 to 60 mg qd, or placebo for 12 weeks. Fluoxetine reduced overt aggression and irritability about 67% more than placebo, as assessed by the Overt Aggression Scale Modified for Outpatients (OAS-M).

 

All subjects met research criteria for IED. A reanalysis suggests that SSRIs may be most effective in moderately aggressive patients (Table 3),¹⁷ whose serotonergic system may be less impaired than that of highly aggressive patients.¹⁸

Mood stabilizers. Impulsively aggressive subjects who do not respond to an SSRI may respond to a mood stabilizer.¹⁹ An antiaggressive response in IED-like subjects has been reported for lithium,²⁰ carbamazepine,²¹ and diphenylhydantoin.²²

Recently, Hollander et al²³ reported greater reduction in overt aggression scores in IED subjects with a DSM cluster B personality disorder who were treated with divalproex, compared with placebo. This study used the same design and outcome measure as our study¹² and included subjects who met both DSM-IV and research criteria for IED.

For unknown reasons, divalproex was no more effective than placebo in IED subjects without cluster B personality disorder. More research is needed to uncover predictors of antiaggressive response in IED subjects.

Unipolar vs. bipolar. McElroy⁹ has suggested using SSRIs (or other antidepressants) as first-line treatment for IED subjects with unipolar affective symptoms and mood stabilizers for those with bipolar affective symptoms. IED subjects without bipolar affective symptoms should be treated first with SSRIs (Algorithm). Preliminary data suggest a role for atypical antipsychotics to treat aggressive behavior in patients with schizophrenia or bipolar disorder, but no empiric data exist.

Beta blockers such as propranolol also may be considered.² However, beta blockers are more difficult to dose and are associated with more burdensome side effects, compared with SSRIs.

Algorithm Suggested 2-pronged approach for treating intermittent explosive disorder

* With or without an anger management program, which may precede drug interventionThe full effects of antiaggressive treatment with an SSRI (E. Coccaro, unpublished observations) or a mood stabilizer¹⁹ may take 3 months to observe^12,20,22,23 and tend to disappear soon after treatment is discontinued.

Therefore, an adequate trial of SSRIs or mood stabilizers is no less than 3 months. If improvement is seen, continue drug treatment indefinitely.

Case report continued.

Mr. P was started on an SSRI. His aggressive outbursts decreased in intensity and frequency over 3 months but were not eliminated. After 6 months he dropped out of treatment, but returned 5 weeks later because his aggressive outbursts had resumed their pre-treatment level.

SSRI treatment was restarted, and Mr. P began a 12-week anger management course of relaxation training, cognitive restructuring, and coping skills training. He gained greater control over his aggressive outbursts and continues monthly medication checks and anger management “booster sessions.”

Related resources

• Galovski T, Blanchard EB, Veazey C. Intermittent explosive disorder and other psychiatric comorbidity among court-referred and self-referred aggressive drivers. Behav Res Ther 2002;40:641-51.
• Olvera RL. Intermittent explosive disorder: epidemiology, diagnosis and management. CNS Drugs 2002;16:517-26.

Drug brand names

• Carbamazepine • Tegretol
• Diphenylhydantoin • Dilantin
• Divalproex • Depakote
• Fluoxetine • Prozac
• Lithium • Lithobid
• Propanolol • Inderal

Disclosure

Dr. Coccaro reports that he receives research grants and serves on the speaker’s bureau or as a consultant to Eli Lilly and Co., Abbott Laboratories, GlaxoSmithKline, and Forrest Laboratories.

Mr. P, age 41, has a “problem with anger.” Since age 17, he has had sudden outbursts of screaming and shouting, with occasional minor damage to objects. These outbursts—including episodes of “road rage”—occur once or more per week and almost daily for months at a time.

Mr. P has also had more violent episodes— sometimes every 2 to 3 months—in which he has punched holes in walls, destroyed a computer with a hammer, and assaulted other people with his fists. These events are not premeditated and are typically triggered by Mr. P’s frustration at not being “perfect” or by others breaking what he considers “general rules of conduct.”

The day before his initial visit, while he was stuck in traffic, Mr. P saw a car speeding down the shoulder. Enraged, he pulled in front of the car so that the driver had to slam on the brakes. He jumped out of his car and approached the other driver, shouting obscenities. The other driver locked her door and tried to ignore Mr. P until he returned to his car. Mr. P noted that this episode “ruined” his day because of his lingering anger and irritability.

Intermittent explosive disorder (IED) is more common and complex than was once thought, based on recent evidence. Recurrent, problematic, impulsive aggression is highly comorbid with other psychiatric conditions—including mood and personality disorders—and undermines social relationships and job performance. Typical characteristics of IED are outlined in Table 1.^1-3

Table 1

Typical characteristics of intermittent explosive disorder

Onset in childhood or adolescence (mean age 15), with average duration ±20 years
Aggressive outbursts:
rapid onset, often without a recognizable prodrome short-lived (<30 minutes) verbal assault, destructive and nondestructive property assault, or physical assault usually in response to minor provocation by close intimate or associate
Some episodes may appear without identifiable provocation
Male to female ratio 3:1, although some data suggest gender parity
Source: Adapted from references 1-3

This article offers updated diagnostic criteria and a two-pronged algorithm that can help you diagnose and treat this aggression disorder.

HOW COMMON IS IED?

DSM-IV states that IED is “apparently rare.” This statement is far from surprising, given the limitations of DSM criteria. Surveys of hospitalized patients in the 1980s found that only 1.1% met DSM-III criteria for IED.⁴ In another study of more than 400 patients seeking treatment for aggression, only 1.8% met DSM-III criteria for IED (although far more would likely have met DSM-IV criteria).⁵

A more recent survey of 411 psychiatric outpatients⁶ found that 3.8% met current and 6.2% met lifetime DSM-IV criteria for IED, using the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Reanalysis of a threefold larger data set from the same study site (Coccaro and Zimmerman, unpublished) yielded the same result.

Far from rare. More recently, our findings from a small sample suggested that the community rate of lifetime IED is about 4% by DSM-IV criteria and 5% by research criteria. In the United States, we estimate that the lifetime rate of IED could be 4.5 to 18 million persons using DSM-IV criteria or 6.7 to 22.2 million using IED research criteria. If so, IED is at least as common as other major psychiatric disorders, including schizophrenia or bipolar illness. The ongoing National Comorbidity Study is expected to produce more definitive community data.

PSYCHIATRIC COMORBIDITY

Axis I disorders. IED is highly comorbid with mood, anxiety, and substance use disorders,^3,7,8 although no causal relationship has been shown

Mood and substance abuse disorders. IED’s age of onset may precede that of mood and substance use disorders, according to analysis of our unpublished data. If so, comorbid IED may not occur in the context of mood or substance use disorders.

Anxiety disorders. We have noted a similar pattern with IED and anxiety disorders, although phobic anxiety disorders (simple or social phobia) tend to manifest earlier than IED. This suggests that early-onset phobic anxiety might be associated with an increased risk of IED in adolescence or young adulthood.

Bipolar disorder. McElroy⁹ has suggested a relationship between IED and bipolar disorder. In some samples, as many as one-half of IED patients (56%) have comorbid bipolar disorder when one includes bipolar II and cyclothymia.³ Moreover, some subjects’ aggressive episodes appear to resemble “microdysphoric manic episodes.”⁹ Other studies,⁸ however, find a much lower rate (10% or less) of IED comorbidity with bipolar illness.

Bipolar disorder overall may not be highly comorbid with IED, although rates may be higher in specialty clinic samples. In individuals with any kind of bipolar disorder, mood stabilizers— rather than selective serotonin reuptake inhibitors (SSRIs)—are probably the better choice as first-line treatment of IED.⁹

 

Axis II disorders. DSM-IV allows IED diagnosis in individuals with borderline or antisocial personality disorder, as long as these cluster B disorders do not better explain the aggressive behavior. How a clinician makes this distinction is not clear; in fact, most clinicians do not diagnose IED in patients with personality disorders, regardless of the clinical picture.

IED comorbidity with borderline or antisocial personality disorders varies with the sample. Persons with personality disorders who seek treatment of aggressive behavior are more likely to have comorbid IED (90%) than those not seeking treatment who are outpatients (50%) or in the community (25%).^1,7

Individuals with personality disorders and IED score higher in aggression and lower in psychosocial function than do similar individuals without IED,⁷ indicating that the additional diagnosis is relevant.

Case report continued.

Mr. P’s outbursts have cost him several friendships, including romantic relationships. He has never advanced at work because he is seen as too volatile to supervise subordinates. Though some of Mr. P’s aggressive outbursts have occurred under the influence of alcohol, most are not related to alcohol or drug use. He has no medical problems and no other psychiatric history.

A full diagnostic evaluation uncovers a personality disorder, not otherwise specified (eight scattered traits from obsessive-compulsive personality disorder and from each of the cluster B personality disorders), and no Axis I condition other than intermittent explosive disorder.

PROBLEMS DEFINING IED

Intermittent explosive disorder is the only DSM diagnosis that applies to persons with histories of recurrent, problematic aggression not caused by another mental or physical disorder. Even so, little research on IED is available. DSM criteria for IED are poorly operationalized and have improved only modestly since the diagnosis was first included in DSM-III. In that revision, IED had four criteria.

“A” criteria specified recurrent outbursts of “seriously assaultive or destructive behavior,” but left unanswered important questions such as:

• What behavior crosses the threshold for seriously” assaultive or destructive?
• Does any physical assault qualify, or only those that cause physical injury (or stigmata)?
• How often or within what time must the behavior occur?

The phrase “recurrent acts of aggression” suggested that at least three acts of aggression were required to reach the threshold, but DSM-III provided no guidelines.

“B” criteria stated that the aggression should be out of proportion to the provocation. But how should one judge this criterion, when provocative stimuli sometimes are clearly sufficient to prompt a justifiably aggressive act?

“C” criteria excluded persons who are aggressive or impulsive between ill-defined “aggressive episodes.” This exclusion was especially limiting because individuals with recurrent, problematic, aggressive behaviors generally are impulsive and aggressive between more-severe outbursts. Excluding those who otherwise met diagnostic criteria for IED led to a spuriously low prevalence rate and limited the number of research subjects. DSM-IV eliminated this criterion but made no other notable changes in IED criteria.

“D” criteria in DSM-III and III-R further restricted the number of individuals who could meet this diagnosis:

• In DSM-III, antisocial personality disorder excluded the diagnosis of IED.
• In DSM-III-R, borderline personality disorder was added as an exclusionary factor.

Because of these restrictions, very few clinically valid cases of IED (individuals meeting A and B criteria) could receive an IED diagnosis.¹⁰

EVOLVING DIAGNOSTIC CRITERIA

By the early 1990s, DSM diagnostic criteria clearly severely restricted the study of recurrent, problematic aggression, even though research since DSM-III had greatly advanced our understanding of human aggression. For example, data linked impulsive aggression to deficits in central serotonergic function and suggested that agents that enhance serotonergic activity could modify this behavior.

Some investigators proposed research criteria for IED (IED-R) so that individuals with recurrent, problematic, impulsive aggression could be identified and studied. Research criteria first published in 1998⁷ proposed six changes/clarifications in IED diagnostic criteria:

Lower-intensity aggression. The scope of aggressive behavior was expanded to include verbal and indirect physical aggression, provided that these behaviors are associated with distress and/or impairment. Data from double-blind, placebo-controlled trials indicated that these lower-intensity (although usually higher frequency) behaviors respond well to treatment with SSRIs.^11,12

Impulsivity. The aggression was specified as impulsive. This change identified individuals with greater liability for deficits in central serotonergic function and excluded individuals with premeditated or criminal aggression.

A minimal frequency of aggression over time was proposed to make the IED diagnosis more reliable and to ensure that persons with only occasional impulsive aggressive outbursts (especially of low severity) were given this diagnosis.

Subjective distress (in the individual) and/or social or occupational dysfunction was proposed so that putatively aggressive individuals are not diagnosed for manifesting behaviors that are not functionally severe.

 

Diagnostic exclusionary criteria were modified so that individuals with:

• antisocial or borderline personality disorder could be diagnosed with IED if otherwise warranted
• aggressive behaviors confined within major depression episodes could not be diagnosed with IED.

This last change recognized that impulsive, aggressive outbursts could point to major depressive disorder.

When the revised criteria were tested in patients seeking treatment for aggression, those who met IED-R criteria were found to exhibit significantly greater aggression and impulsivity (using validated scales) and lower global functioning than those who did not.⁷ Statistical adjustments made to account for aggression score differences eliminated the difference in global functioning, which suggested a direct link between aggression and global function in individuals with IED-R.

Two patterns. Later research uncovered at least patterns of aggressive outbursts:

• low intensity at high frequency (such as verbal arguments or door slamming approximately twice weekly)
• high intensity at low frequency (such as physical aggression resulting in injury or destruction of nontrivial property at least three times per year).

Data revealed that 69% of individuals with IED-like histories displayed both aggression patterns, 20% displayed only the high-intensity/low-frequency pattern, and 11% displayed only the low-intensity/high-frequency pattern.

Because further analysis revealed no important differences between these groups in measures of aggression and impulsivity, IED-R criteria were revised to include both patterns in the “A” criteria. This revision integrated the essences of IED-R and DSM criteria into one diagnostic set (Table 2).

INFLUENCE OF HEREDITY

No twin or adoption studies of IED have been performed. However, family history data suggest that IED (or IED-type behavior) is familial. I recently conducted a blinded, controlled, family history study using IED-R criteria and found a significantly elevated risk for IED (p < 0.01) in relatives of persons with a history of IED (26%), compared with non-IED controls (8%). Comorbid conditions did not affect the risk among the IED subjects or their relatives, suggesting that IED is familial and independent of other conditions.¹³

Nearly all studies of aggression’s biology and treatment have measured aggression as a dimensional variable along a continuous scale from low to high.¹⁴ Our studies have allowed us to explore biological and treatment response correlates. In preliminary analyses, we have found that the maximal prolactin response to d-fenfluramine challenge and the number of platelet serotonin transporter binding sites are:

• reduced in subjects meeting research criteria for IED
• inversely correlated with dimensional measures of impulsive aggression.

Table 2

Updated diagnostic criteria for intermittent explosive disorder

A. Recurrent incidents of aggression manifest as either:
1. Verbal or physical aggression towards other people, animals, or property occurring twice weekly on average for 1 month
OR
2. Three episodes involving physical assault against other people or destruction of property over a 1-year period
B. The degree of aggressiveness expressed is grossly out of proportion to the provocation or any precipitating psychosocial stressors
C. The aggressive behavior is generally not premeditated (ie, is impulsive) and is not committed to achieve a tangible objective (such as money, power, intimidation, etc.)
D. The aggressive behavior causes marked distress in the individual or impairs occupational or interpersonal functioning
E. The aggressive behavior is not better explained by another mental disorder (such as a major depressive/manic/psychotic disorder, attention-deficit/hyperactivity disorder, general medical condition [head trauma, Alzheimer’s disease], or due to the direct physiologic effects of a substance)
Source: Adapted from reference 7

Earlier, Virkkunen et al¹⁵ reported reduced cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in persons diagnosed with IED based on DSM-III criteria, compared with persons who were not diagnosed with IED and those who demonstrated nonimpulsive aggression.

TREATING IED

Cognitive therapy. Few double-blind, randomized, placebo-controlled trials of any treatments for IED have been published. Trials using cognitive-behavioral approaches have reduced self-rated anger and its expression in young adults with anger disorders.¹⁶ Although many of these subjects may have had IED, it is not known if this approach works in IED.

Table 3

Characteristic behaviors of aggressive individuals*

Severity	Behaviors
Mildly aggressive	Occasional verbal arguments and/or temper tantrums
Moderately aggressive	Frequent verbal arguments and temper tantrums (about twice weekly on average), occasional destruction of property, rare or occasional physical assault against others (usually without injury)
Highly aggressive	Frequent verbal arguments and temper tantrums (about twice weekly) and/or more than occasional destruction of property or physical assault against others, sometimes with injury
* Characteristics given are descriptive and not based on data.

Drug therapy. SSRIs. A trial by this author using fluoxetine showed that impulsive aggressive behavior responds to treatment that targets the central serotonergic system.¹² Forty subjects with personality disorders and histories of impulsive aggression received fluoxetine, 20 to 60 mg qd, or placebo for 12 weeks. Fluoxetine reduced overt aggression and irritability about 67% more than placebo, as assessed by the Overt Aggression Scale Modified for Outpatients (OAS-M).

 

All subjects met research criteria for IED. A reanalysis suggests that SSRIs may be most effective in moderately aggressive patients (Table 3),¹⁷ whose serotonergic system may be less impaired than that of highly aggressive patients.¹⁸

Mood stabilizers. Impulsively aggressive subjects who do not respond to an SSRI may respond to a mood stabilizer.¹⁹ An antiaggressive response in IED-like subjects has been reported for lithium,²⁰ carbamazepine,²¹ and diphenylhydantoin.²²

Recently, Hollander et al²³ reported greater reduction in overt aggression scores in IED subjects with a DSM cluster B personality disorder who were treated with divalproex, compared with placebo. This study used the same design and outcome measure as our study¹² and included subjects who met both DSM-IV and research criteria for IED.

For unknown reasons, divalproex was no more effective than placebo in IED subjects without cluster B personality disorder. More research is needed to uncover predictors of antiaggressive response in IED subjects.

Unipolar vs. bipolar. McElroy⁹ has suggested using SSRIs (or other antidepressants) as first-line treatment for IED subjects with unipolar affective symptoms and mood stabilizers for those with bipolar affective symptoms. IED subjects without bipolar affective symptoms should be treated first with SSRIs (Algorithm). Preliminary data suggest a role for atypical antipsychotics to treat aggressive behavior in patients with schizophrenia or bipolar disorder, but no empiric data exist.

Beta blockers such as propranolol also may be considered.² However, beta blockers are more difficult to dose and are associated with more burdensome side effects, compared with SSRIs.

Algorithm Suggested 2-pronged approach for treating intermittent explosive disorder

* With or without an anger management program, which may precede drug interventionThe full effects of antiaggressive treatment with an SSRI (E. Coccaro, unpublished observations) or a mood stabilizer¹⁹ may take 3 months to observe^12,20,22,23 and tend to disappear soon after treatment is discontinued.

Therefore, an adequate trial of SSRIs or mood stabilizers is no less than 3 months. If improvement is seen, continue drug treatment indefinitely.

Case report continued.

Mr. P was started on an SSRI. His aggressive outbursts decreased in intensity and frequency over 3 months but were not eliminated. After 6 months he dropped out of treatment, but returned 5 weeks later because his aggressive outbursts had resumed their pre-treatment level.

SSRI treatment was restarted, and Mr. P began a 12-week anger management course of relaxation training, cognitive restructuring, and coping skills training. He gained greater control over his aggressive outbursts and continues monthly medication checks and anger management “booster sessions.”

Related resources

• Galovski T, Blanchard EB, Veazey C. Intermittent explosive disorder and other psychiatric comorbidity among court-referred and self-referred aggressive drivers. Behav Res Ther 2002;40:641-51.
• Olvera RL. Intermittent explosive disorder: epidemiology, diagnosis and management. CNS Drugs 2002;16:517-26.

Drug brand names

• Carbamazepine • Tegretol
• Diphenylhydantoin • Dilantin
• Divalproex • Depakote
• Fluoxetine • Prozac
• Lithium • Lithobid
• Propanolol • Inderal

Disclosure

Dr. Coccaro reports that he receives research grants and serves on the speaker’s bureau or as a consultant to Eli Lilly and Co., Abbott Laboratories, GlaxoSmithKline, and Forrest Laboratories.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

 

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

Serious medical conditions  History of seizures  Increased intracranial pressure  Serious head trauma
Myocardial infarction within the past 6 months
Pregnancy or childbearing potential (unless reliable contraception is being used)
Intracranial metallic implants
Pacemakers or other implanted devices

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

 

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

 

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

Serious medical conditions  History of seizures  Increased intracranial pressure  Serious head trauma
Myocardial infarction within the past 6 months
Pregnancy or childbearing potential (unless reliable contraception is being used)
Intracranial metallic implants
Pacemakers or other implanted devices

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

 

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.

Using magnets to improve health is sometimes hawked in dubious classified ads and “infomercials.” However, a legitimate use of magnetism—repetitive transcranial magnetic stimulation (rTMS)—is showing promise in treating severe depression (Box) ^1-4 and other psychiatric disorders.

Patients or their families are likely to ask psychiatrists about rTMS as more becomes known about this investigational technology. Drawing from our experience and the evidence, we offer an update on whether rTMS may be an alternative for treating depression and address issues that must be resolved before it could be used in clinical practice.

WHAT IS RTMS?

rTMS consists of a series of magnetic pulses produced by a stimulator, which can be adjusted for:

• coil type and placement
• stimulation site, intensity, frequency, and number
• amount of time between stimulations
• treatment duration.

Box

Coil type and placement. Initial studies involved stimulation—typically low-frequency—over the vertex, but most subsequent rTMS trials in depression have stimulated the left dorsolateral prefrontal cortex. Neuroimaging studies have shown prefrontal functioning abnormalities in depressed subjects, and it is hypothesized that stimulating this area (plus possible distal effects) may produce an antidepressant effect.⁵

Various configurations have been used, but circular and figure-eight-shaped coils are most common. These flat coils are made of tightly wound ferromagnetic material such as copper, enclosed in a heavy plastic cover. With the figure-eight coil, the intersection of the two loops produces the strongest magnetic field.

Stimulation site. Stimulation intensity depends on the individual’s motor threshold, and the site can be determined visually or electrophysiologically.

• With the visual method, the motor threshold over the left primary motor cortex site for the first dorsal interosseous muscle (FDI) or the abductor pollius brevis (APB) is determined by iteration. This involves placing the coil at a progression of sites and increasing stimulation intensity until reliable (in 5 of 10 stimulations) contractions are seen in the right FDI or APB.
• Similarly, the electrophysiologic method uses 5 of 10 motorevoked potentials of 50 microvolts to locate the site.

The only small trial that compared visual and electrophysiologic site determination showed similar results with both methods.⁶ The most common stimulation site is the left dorsolateral prefrontal cortex, 5 cm anterior and parasagittal to the FDI or APB motor cortex. Alternately, frameless stereotactic systems or the international 10-20 proportional system used in EEG labs have been recommended to target sites more accurately.

Stimulus intensity. Each individual’s motor threshold determines stimulus intensity. Using functional MRI studies, researchers from the Medical University of South Carolina concluded that higher stimulation intensity relative to the motor threshold may have a more robust effect, as the magnetic field declines with distance from the coil.⁷ However, intensities >120% of the motor threshold are generally avoided because of possible increased seizure risk.⁹

Frequency of stimulation. Most researchers apply frequencies of 1 to 20 Hz over the left dorsolateral prefrontal cortex, but also use lower frequencies (<1 Hz) over the right dorsolateral prefrontal cortex. Using higher frequencies in major depression is attractive in theory because of:

• the reported association of decreased regional cerebral blood flow with hypometabolism in the left dorsolateral prefrontal cortex
• higher-frequency stimulation’s ability to produce temporary excitation and neuronal depolarization.

Number of stimulations. The number of stimulations is determined by frequency (Hz) and stimulation train duration (for example, 10 Hz for 5 seconds equals 50 stimulations). A typical treatment session incorporates 10 to 30 stimulation trains several seconds apart (the inter-train interval). Thus, a typical session delivers 1,000 to 1,200 stimulations. In studies of unmedicated depressed patients, the total number of stimulations has varied from 8,000 to 32,000 per treatment course.

 

Duration between two stimulation trains. Chen et al have demonstrated that shorter (<1 second) inter-train intervals increase seizure risk with higher frequencies (such as 20 Hz) and intensities (>100% of motor threshold) of stimulation.⁹ Based on their studies with healthy volunteers, they recommended several “safe” ranges (such as 5 seconds at 110% of motor threshold). Most trials use 30- to 60-second inter-train intervals.

Most treatments continue 2 to 4 weeks, Monday through Friday, although more frequent treatments are being studied.

EFFICACY FOR DEPRESSION

Most studies of rTMS in depression have compared real rTMS to a sham control or electroconvulsive therapy (ECT).

In earlier studies, the sham procedure typically involved tilting the coil away from the skull. This method has been questioned, however, because of evidence of neuronal depolarization.¹⁰

More recent sham coils mimic the real coils’ sound and sensation, without magnetic stimulation.

Despite these methodologic problems and some mixed results, depressed patients receiving rTMS show more favorable results than those receiving sham rTMS.^11,12 Several meta-analyses have attempted to quantify rTMS’ efficacy for depression:

• Holtzheimer et al concluded that rTMS was statistically superior to sham rTMS, but the clinical significance of these findings was modest in a population of mostly outpatients with less-severe depression.¹³
• Burt et al found a statistically strong antidepressant effect, but its magnitude varied and few of the studies yielded a substantial clinical response or remission. The team also noted that rTMS’ long-term efficacy or adverse effects are unknown.¹⁴
• Kozel et al concluded that left prefrontal rTMS rendered a significant antidepressant effect with measurable clinical improvement.¹⁵
• Gershon et al¹⁶ supported an antidepressant effect for rTMS when compared with sham rTMS or ECT.

Ongoing rTMS research includes subjects with many types of mild to severe psychiatric illnesses, including major depression, obsessive-compulsive disorder, and psychosis. Typically, patients referred for experimental approaches have not responded to or tolerated available treatments. Exclusion criteria used by most rTMS studies are listed in the Table.

Table

Medical conditions that preclude use of rTMS

Serious medical conditions  History of seizures  Increased intracranial pressure  Serious head trauma
Myocardial infarction within the past 6 months
Pregnancy or childbearing potential (unless reliable contraception is being used)
Intracranial metallic implants
Pacemakers or other implanted devices

rTMS vs. ECT. Four randomized, controlled trials have compared rTMS with ECT for treating severely ill, often medication-resistant patients.^17-20 Although their methodologies differed, all four studies concluded that rTMS and ECT offer similar efficacy, except that rTMS may be less effective for treating psychotic depression.

One study found ECT more effective than rTMS for psychotic depression, although the patients who received ECT were also treated with antipsychotics and/or antidepressants.¹⁷ Our study,¹⁹ which did not use these agents, has not corroborated this observation. Preliminary data also indicate comparable relapse rates following acute ECT and rTMS when subjects are followed on maintenance medication.²¹

ADVERSE EFFECTS

The potential adverse effects of new treatments must always be considered. Thus far, rTMS appears to produce minimal, relatively benign complications, including:

• mild discomfort at the stimulation site
• localized muscle twitching during stimulation
• mild post-treatment headaches—believed caused by muscle contractions—which usually respond to aspirin or acetaminophen
• treatment stimulation-related seizures (rarely).⁸

The rTMS device makes a loud clicking noise, and subjects wear protective ear plugs during treatment.

Patient experience. The first rTMS session—during which the patient’s motor threshold is determined—can last up to 45 minutes. Subsequent sessions are usually 15 to 20 minutes. Patients are typically apprehensive before the first session but become more relaxed with experience and tolerate the treatments easily.

During the procedure, many patients describe a tapping sensation on the forehead, and some experience slight muscle twitching around the eye or corner of the mouth. As the coil warms, the skin it touches sometimes flushes pink, although this does not seem to bother our patients. They can return to their daily routines immediately after a session.

rTMS for major depression. In our experience, rTMS may help patients with major depression. For example, one patient diagnosed with a major depressive episode with psychotic features was referred to our study comparing rTMS with ECT.¹⁹ Her depression had lasted several months, with partial response to ECT treatments. She signed informed consent and was randomly assigned to receive rTMS treatment.

At study admission, the patient’s Hamilton Depression Rating Scale (HDRS) score was 48, indicating moderate to severe depression. Following 10 rTMS sessions, her HDRS score had dropped to 2, with remission of symptoms. No follow-up results were documented.

Cognitive effects. Whereas mood disorders are associated with medication-independent neuropsychological deficits, most studies have found no adverse cognitive effects with rTMS.²² Indeed, some of our rTMS patients have improved in certain cognitive tests, although this may be explained by test-retest effects or better attention and concentration associated with mood improvement.

 

Figure Potential roles for rTMS in treating major depression

Solid lines represent current standards of practice. Dotted lines represent hypothetical roles for rTMS.

Source: Adapted and reprinted with permission from Dowd et al. Is repetitive transcranial magnetic stimulation an alternative to ECTfor the treatment of depression? Contemp Psychiatry 2002;1:1-10.

POTENTIAL ROLE FOR rTMS

Today’s standard treatment of major depressive episodes begins with an antidepressant (plus an antipsychotic, if necessary) and proceeds to augmentation strategies if response is insufficient. rTMS may one day become an augmentation or monotherapy option for patients who do not respond sufficiently to standard treatments (Figure).

ECT treatment may be initiated if a patient has had a prior good response to ECT, is intolerant to medication, or prefers ECT. In that case, rTMS may be used as an alternate initial treatment or with ECT. Thus, rTMS may be used:

• to augment antidepressants
• as an alternative to antidepressants or ECT
• or sequentially with ECT.

Before that can happen, however, optimal treatment parameters need to be clarified by larger, well-designed, controlled studies comparing rTMS to a valid sham treatment, antidepressants, and ECT.

Related resources

• International Society for Transcranial Stimulation. www.ists.unibe.ch/
• Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital.

Disclosure

The authors report that they have no proprietary interest in the technology discussed in this article.

Psychiatrists often treat patients with irritable bowel syndrome (IBS) and an accompanying mental illness. Knowledge of available treatments and communication with the referring doctor are crucial to treating both the IBS symptoms and the comorbidity.

This article presents three cases that illustrate the challenges of identifying target symptoms, avoiding drug-drug interactions, ruling out serious underlying medical problems, and formulating treatment.

WHO GETS IBS?

Approximately 12% of the United States population reports IBS symptoms (abdominal pain, bloating, altered bowel habits).¹ These symptoms begin before age 35 in most patients and during childhood in some. Onset after age 65 is rare.

IBS is common among patients with alcohol abuse disorder (32%),² chronic fatigue syndrome (92%), fibromyalgia (77%), or temporomandibular joint syndrome (64%).³ Seventy percent of patients with IBS are women.⁴ Chronic pelvic pain, dyspareunia, dysmenorrhea, or a history of abdominal surgeries are risk factors for IBS in women.

LINK BETWEEN IBS AND MENTAL ILLNESS

Although mental illness often coexists with IBS, no cause-effect relationship has been shown.⁵

IBS is often preceded by stressful life events, such as family death or divorce,³ and some believe IBS is a precursor to numerous psychiatric disorders. Generalized anxiety disorder, major depression, panic disorder, social phobia, somatization disorder, or dysthymia have been diagnosed in most IBS patients.²

CASE 1: IBS AND DEPRESSION

Ms. R, age 55, has had IBS for 10 years. She has occasional diarrhea and abdominal cramps relieved by bowel movements. She is taking a bulking agent but still sometimes suffers abdominal pain.

She is referred to a psychiatrist after complaining of fatigue, loss of interest in hobbies, and crying spells for 2 months. She denies suicidal ideations. Her referring physician reports that she is taking conjugated estrogens to manage menopause symptoms. She denies any recent stressful life events. Thyroid function, glucose, and CBC are normal.

The challenge: Deciding which to treat first—the IBS symptoms or the depression—and how.

Discussion: The predominant symptom (in Ms. R’s case, abdominal pain) can help determine choice of medication. Bulk-forming agents, antispasmodics, barbiturates, benzodiazepines, and serotonin reuptake inhibitors have historically been used to treat IBS,⁶ but scant evidence supports their use.

Obtaining a thorough prescription history from the primary care physician, OB/GYN, and other treatment team members is critical before formulating a treatment plan. Ms. R’s estrogen use will not affect the choice of psychotropic or IBS medication because there are no significant interactions between estrogen and these classes of drugs.

Ms. R’s abdominal pain and depression can be treated simultaneously. Randomized, controlled trials have demonstrated that tricyclic antidepressants reduce abdominal pain and that behavioral therapy (relaxation therapy, hypnotherapy, and cognitive-behavioral therapy) may relieve individual IBS symptoms.⁷

Case 1 concluded: After reviewing Ms. R’s medications, the psychiatrist starts:

• desipramine, 50 mg at bedtime, to minimize anticholinergic side effects
• and short-term psychotherapy, which helped her identify support mechanisms and ways to better balance her life stresses.

After 6 weeks, her Beck Depression Inventory score improved from 30 at baseline to 8. She reports her abdominal pain is “the best it has been in 10 years.” Six months after diagnosis, she continues to take desipramine and is doing well.

CASE 2: IBS, DEPRESSION, AND PSYCHOSIS

Ms. H, age 32, is referred to a psychiatrist for treatment of depression with paranoid features.

Four years ago, a gastroenterologist diagnosed her as having IBS. She experiences frequent diarrhea and lower abdominal cramping. For 2 years she has been taking the antimuscarinic dicyclomine, 10 mg tid, which has provided some relief from her cramps. An estimated 20 diarrhea attacks per day leaves her housebound much of the time, however.

She reports fatigue, loss of interest in hobbies across 2 months, and paranoid thinking. She denies hallucinations or delusions but believes that her teenage children are discussing her “sickness” and plotting to “drive her crazy.” She is not suicidal.

The challenge: Treating Ms. H’s depression and paranoia while avoiding drug-drug interactions.

Discussion: Adverse drug-drug interactions can occur when prescribing psychotropics to patients with IBS (Table 1). Additive constipation, diarrhea, abdominal pain, and sedation are common interactions between psychotropics and the 5-HT3 antagonists and 5HT4 agonists commonly prescribed for IBS.

Table 1

Interactions between psychotropics and agents prescribed for IBS

	Antispasmodics	Benzodiazepines	SSRIs	Tricyclics
MAOIs	Additive sedation	Additive dizziness, sedation, dry mouth,	Contraindicated–hyperpyrexia and severe neurologic effects	Contraindicated–hyperpyrexia, seizures, and death
SSRIs	Additive sedation	Additive sedation	—-	Increased tricyclic levels with concurrent use
Tricyclics	Additive sedation, dry mouth	Additive sedation	Additive sedation, dry mouth, increased tricyclic levels	—-
Anticonvulsants	Additive sedation	Additive sedation	Increased levels of anticonvulsants	Additive sedation, dry mouth, constipation
Benzodiazepines	Additive sedation	—-	Additive sedation and dry mouth	Additive sedation
Buspirone	Additive sedation, dizziness	Additive sedation	Additive sedation, dizziness, nausea	Additive sedation, dry mouth, constipation, increased tricyclic level
Traditional antipsychotics	Additive sedation, CNS effects	Additive sedation, CNS effects	Additive sedation, dizziness	Additive sedation and anticholinergic effects; increased tricyclic level
Atypical antipsychotics	Additive sedation, CNS effects	Contraindicated–respiratory and cardiovascular collapse	Elevated antipsychotic levels	Levels of both drugs increased
Aripiprazole	Somnolence,constipation	Additive sedation	Increased blood levels of aripiprazole	Increased sedation and anticholinergic effects
Psychotropics and 5-HT3 antagonists taken concomitantly typically lead to additive constipation and abdominal pain.
Psychotropics and 5-HT4 agonists taken concomitantly typically lead to additive diarrhea and/or abdominal pain.
Source: Physician’s Desk Reference. Mobile PDR release version 32. Database version 437. Montvale, NJ: Thomson Healthcare 2003.

 

Box

Other than fiber supplements, most traditional IBS medications are sedating and are associated with anticholinergic side effects. In Ms. H’s case, extreme caution is necessary before prescribing an antidepressant or antipsychotic because of dicyclomine’s additive sedating effects.

Case 2 concluded: After a thorough initial patient interview, the psychiatrist elects to treat Ms. H’s major depression with an antidepressant but delays the use of an antipsychotic to avoid additive sedation.

After talking with Ms. H’s family physician, the psychiatrist stops her dicyclomine and starts sertraline, 100 mg/d. She tolerates the sertraline well and the dosage is titrated across 1 month to 200 mg/d.

Four weeks later, Ms. H’s Beck Depression Inventory score has improved from 26 at baseline to 5, but her paranoid thoughts and frequent diarrhea persist. The psychiatrist adds low-dose olanzapine (5 mg at bedtime) to minimize extrapyramidal side effects. One month later, her depression and paranoia have resolved.

Ms. H’s gastroenterologist instructs her to begin taking alosetron, 1 mg bid, for her continued frequent diarrhea. Adding this agent to her sertraline/olanzapine regimen can lead to additive constipation and abdominal pain, so the psychiatrist monitors her psychiatric medications. One month later, she reports that her affect is much improved and her diarrhea is “gone.”

CASE 3: DEPRESSION AND ABDOMINAL PAIN

Mr. J, age 52, has had depression for 1 year. His depressive symptoms have improved significantly on fluoxetine, 20 mg/d; he once again enjoys life and has a more positive outlook.

The patient was in reasonably good health until about 1 month ago, when he began to experience abdominal pain. He has lost 14 lbs over the past month. He is not taking other medications.

The challenge: Find the cause of Mr. J’s persistent abdominal pain without undermining depression therapy.

Discussion: Although Mr. J’s symptoms might be side effects of fluoxetine, his abdominal pain and weight loss >10 lbs within 1 month are cause for concern. The American College of Gastroenterology has identified six alarm symptoms that could point to a serious medical problem in patients with severe abdominal pain (Box).⁷

Patients who exhibit any of these symptoms should be referred for endoscopic and stool studies. Colon cancer screening should be considered for all patients age 50 and older.

Patients with IBS usually present first to their primary care physicians with abdominal pain and altered bowel habits. These symptoms can occur in many gastrointestinal and systemic illnesses (Table 2).⁸

Table 2

Diagnosing irritable bowel syndrome: What to rule out

Differential diagnosis	Examples
Inflammatory bowel disease	Crohn’s disease, ulcerative colitis
Medication effects	Laxatives, constipating agents
Infections	Parasitic, bacterial, viral, opportunistic
Malabsorption syndromes	Celiac disease, pancreatic insufficiency
Endocrine disorders	Hypothyroidism, hyperthyroidism, diabetes, Addison’s disease
Endocrine tumors (extremely uncommon)	Gastrinoma, carcinoid
Colorectal carcinoma	Adenocarcinoma, villous adenoma
Intestinal pseudo-obstruction	Diabetes, scleroderma
Lactose intolerance	—-
Psychiatric disorders	Depression, anxiety, somatization disorders
Source: Dalton CB, Drossman D. Am Fam Physician. 1997;55(3):875-80.

Case 3 concluded: The psychiatrist and primary care physician consult a gastroenterologist, who performs a colonoscopy and identifies a resectable Duke’s Class B adenocarcinoma in the transverse colon. A partial colectomy is performed.

Three years later, Mr. J is cancer-free and his depression is stable. The psychiatrist advises him to keep taking fluoxetine, 20 mg/d, because the stress of his cancer therapy increases the risk of depression recurrence.

Related resources

• National Institute of Diabetes and Digestive and Kidney Diseases —Irritable Bowel Syndrome www.niddk.nih.gov/health/digest/pubs/irrbowel/irrbowel.htm

Drug brand names

• Alosetron • Lotronex
• Aripiprazole • Abilify
• Buspirone • BuSpar
• Desipramine • Norpramin
• Dicyclomine • Bentyl
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Sertraline • Zoloft

Disclosure

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

Psychiatrists often treat patients with irritable bowel syndrome (IBS) and an accompanying mental illness. Knowledge of available treatments and communication with the referring doctor are crucial to treating both the IBS symptoms and the comorbidity.

This article presents three cases that illustrate the challenges of identifying target symptoms, avoiding drug-drug interactions, ruling out serious underlying medical problems, and formulating treatment.

WHO GETS IBS?

Approximately 12% of the United States population reports IBS symptoms (abdominal pain, bloating, altered bowel habits).¹ These symptoms begin before age 35 in most patients and during childhood in some. Onset after age 65 is rare.

IBS is common among patients with alcohol abuse disorder (32%),² chronic fatigue syndrome (92%), fibromyalgia (77%), or temporomandibular joint syndrome (64%).³ Seventy percent of patients with IBS are women.⁴ Chronic pelvic pain, dyspareunia, dysmenorrhea, or a history of abdominal surgeries are risk factors for IBS in women.

LINK BETWEEN IBS AND MENTAL ILLNESS

Although mental illness often coexists with IBS, no cause-effect relationship has been shown.⁵

IBS is often preceded by stressful life events, such as family death or divorce,³ and some believe IBS is a precursor to numerous psychiatric disorders. Generalized anxiety disorder, major depression, panic disorder, social phobia, somatization disorder, or dysthymia have been diagnosed in most IBS patients.²

CASE 1: IBS AND DEPRESSION

Ms. R, age 55, has had IBS for 10 years. She has occasional diarrhea and abdominal cramps relieved by bowel movements. She is taking a bulking agent but still sometimes suffers abdominal pain.

She is referred to a psychiatrist after complaining of fatigue, loss of interest in hobbies, and crying spells for 2 months. She denies suicidal ideations. Her referring physician reports that she is taking conjugated estrogens to manage menopause symptoms. She denies any recent stressful life events. Thyroid function, glucose, and CBC are normal.

The challenge: Deciding which to treat first—the IBS symptoms or the depression—and how.

Discussion: The predominant symptom (in Ms. R’s case, abdominal pain) can help determine choice of medication. Bulk-forming agents, antispasmodics, barbiturates, benzodiazepines, and serotonin reuptake inhibitors have historically been used to treat IBS,⁶ but scant evidence supports their use.

Obtaining a thorough prescription history from the primary care physician, OB/GYN, and other treatment team members is critical before formulating a treatment plan. Ms. R’s estrogen use will not affect the choice of psychotropic or IBS medication because there are no significant interactions between estrogen and these classes of drugs.

Ms. R’s abdominal pain and depression can be treated simultaneously. Randomized, controlled trials have demonstrated that tricyclic antidepressants reduce abdominal pain and that behavioral therapy (relaxation therapy, hypnotherapy, and cognitive-behavioral therapy) may relieve individual IBS symptoms.⁷

Case 1 concluded: After reviewing Ms. R’s medications, the psychiatrist starts:

• desipramine, 50 mg at bedtime, to minimize anticholinergic side effects
• and short-term psychotherapy, which helped her identify support mechanisms and ways to better balance her life stresses.

After 6 weeks, her Beck Depression Inventory score improved from 30 at baseline to 8. She reports her abdominal pain is “the best it has been in 10 years.” Six months after diagnosis, she continues to take desipramine and is doing well.

CASE 2: IBS, DEPRESSION, AND PSYCHOSIS

Ms. H, age 32, is referred to a psychiatrist for treatment of depression with paranoid features.

Four years ago, a gastroenterologist diagnosed her as having IBS. She experiences frequent diarrhea and lower abdominal cramping. For 2 years she has been taking the antimuscarinic dicyclomine, 10 mg tid, which has provided some relief from her cramps. An estimated 20 diarrhea attacks per day leaves her housebound much of the time, however.

She reports fatigue, loss of interest in hobbies across 2 months, and paranoid thinking. She denies hallucinations or delusions but believes that her teenage children are discussing her “sickness” and plotting to “drive her crazy.” She is not suicidal.

The challenge: Treating Ms. H’s depression and paranoia while avoiding drug-drug interactions.

Discussion: Adverse drug-drug interactions can occur when prescribing psychotropics to patients with IBS (Table 1). Additive constipation, diarrhea, abdominal pain, and sedation are common interactions between psychotropics and the 5-HT3 antagonists and 5HT4 agonists commonly prescribed for IBS.

Table 1

Interactions between psychotropics and agents prescribed for IBS

	Antispasmodics	Benzodiazepines	SSRIs	Tricyclics
MAOIs	Additive sedation	Additive dizziness, sedation, dry mouth,	Contraindicated–hyperpyrexia and severe neurologic effects	Contraindicated–hyperpyrexia, seizures, and death
SSRIs	Additive sedation	Additive sedation	—-	Increased tricyclic levels with concurrent use
Tricyclics	Additive sedation, dry mouth	Additive sedation	Additive sedation, dry mouth, increased tricyclic levels	—-
Anticonvulsants	Additive sedation	Additive sedation	Increased levels of anticonvulsants	Additive sedation, dry mouth, constipation
Benzodiazepines	Additive sedation	—-	Additive sedation and dry mouth	Additive sedation
Buspirone	Additive sedation, dizziness	Additive sedation	Additive sedation, dizziness, nausea	Additive sedation, dry mouth, constipation, increased tricyclic level
Traditional antipsychotics	Additive sedation, CNS effects	Additive sedation, CNS effects	Additive sedation, dizziness	Additive sedation and anticholinergic effects; increased tricyclic level
Atypical antipsychotics	Additive sedation, CNS effects	Contraindicated–respiratory and cardiovascular collapse	Elevated antipsychotic levels	Levels of both drugs increased
Aripiprazole	Somnolence,constipation	Additive sedation	Increased blood levels of aripiprazole	Increased sedation and anticholinergic effects
Psychotropics and 5-HT3 antagonists taken concomitantly typically lead to additive constipation and abdominal pain.
Psychotropics and 5-HT4 agonists taken concomitantly typically lead to additive diarrhea and/or abdominal pain.
Source: Physician’s Desk Reference. Mobile PDR release version 32. Database version 437. Montvale, NJ: Thomson Healthcare 2003.

 

Box

Other than fiber supplements, most traditional IBS medications are sedating and are associated with anticholinergic side effects. In Ms. H’s case, extreme caution is necessary before prescribing an antidepressant or antipsychotic because of dicyclomine’s additive sedating effects.

Case 2 concluded: After a thorough initial patient interview, the psychiatrist elects to treat Ms. H’s major depression with an antidepressant but delays the use of an antipsychotic to avoid additive sedation.

After talking with Ms. H’s family physician, the psychiatrist stops her dicyclomine and starts sertraline, 100 mg/d. She tolerates the sertraline well and the dosage is titrated across 1 month to 200 mg/d.

Four weeks later, Ms. H’s Beck Depression Inventory score has improved from 26 at baseline to 5, but her paranoid thoughts and frequent diarrhea persist. The psychiatrist adds low-dose olanzapine (5 mg at bedtime) to minimize extrapyramidal side effects. One month later, her depression and paranoia have resolved.

Ms. H’s gastroenterologist instructs her to begin taking alosetron, 1 mg bid, for her continued frequent diarrhea. Adding this agent to her sertraline/olanzapine regimen can lead to additive constipation and abdominal pain, so the psychiatrist monitors her psychiatric medications. One month later, she reports that her affect is much improved and her diarrhea is “gone.”

CASE 3: DEPRESSION AND ABDOMINAL PAIN

Mr. J, age 52, has had depression for 1 year. His depressive symptoms have improved significantly on fluoxetine, 20 mg/d; he once again enjoys life and has a more positive outlook.

The patient was in reasonably good health until about 1 month ago, when he began to experience abdominal pain. He has lost 14 lbs over the past month. He is not taking other medications.

The challenge: Find the cause of Mr. J’s persistent abdominal pain without undermining depression therapy.

Discussion: Although Mr. J’s symptoms might be side effects of fluoxetine, his abdominal pain and weight loss >10 lbs within 1 month are cause for concern. The American College of Gastroenterology has identified six alarm symptoms that could point to a serious medical problem in patients with severe abdominal pain (Box).⁷

Patients who exhibit any of these symptoms should be referred for endoscopic and stool studies. Colon cancer screening should be considered for all patients age 50 and older.

Patients with IBS usually present first to their primary care physicians with abdominal pain and altered bowel habits. These symptoms can occur in many gastrointestinal and systemic illnesses (Table 2).⁸

Table 2

Diagnosing irritable bowel syndrome: What to rule out

Differential diagnosis	Examples
Inflammatory bowel disease	Crohn’s disease, ulcerative colitis
Medication effects	Laxatives, constipating agents
Infections	Parasitic, bacterial, viral, opportunistic
Malabsorption syndromes	Celiac disease, pancreatic insufficiency
Endocrine disorders	Hypothyroidism, hyperthyroidism, diabetes, Addison’s disease
Endocrine tumors (extremely uncommon)	Gastrinoma, carcinoid
Colorectal carcinoma	Adenocarcinoma, villous adenoma
Intestinal pseudo-obstruction	Diabetes, scleroderma
Lactose intolerance	—-
Psychiatric disorders	Depression, anxiety, somatization disorders
Source: Dalton CB, Drossman D. Am Fam Physician. 1997;55(3):875-80.

Case 3 concluded: The psychiatrist and primary care physician consult a gastroenterologist, who performs a colonoscopy and identifies a resectable Duke’s Class B adenocarcinoma in the transverse colon. A partial colectomy is performed.

Three years later, Mr. J is cancer-free and his depression is stable. The psychiatrist advises him to keep taking fluoxetine, 20 mg/d, because the stress of his cancer therapy increases the risk of depression recurrence.

Related resources

• National Institute of Diabetes and Digestive and Kidney Diseases —Irritable Bowel Syndrome www.niddk.nih.gov/health/digest/pubs/irrbowel/irrbowel.htm

Drug brand names

• Alosetron • Lotronex
• Aripiprazole • Abilify
• Buspirone • BuSpar
• Desipramine • Norpramin
• Dicyclomine • Bentyl
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Sertraline • Zoloft

Disclosure

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

Psychiatrists often treat patients with irritable bowel syndrome (IBS) and an accompanying mental illness. Knowledge of available treatments and communication with the referring doctor are crucial to treating both the IBS symptoms and the comorbidity.

This article presents three cases that illustrate the challenges of identifying target symptoms, avoiding drug-drug interactions, ruling out serious underlying medical problems, and formulating treatment.

WHO GETS IBS?

Approximately 12% of the United States population reports IBS symptoms (abdominal pain, bloating, altered bowel habits).¹ These symptoms begin before age 35 in most patients and during childhood in some. Onset after age 65 is rare.

IBS is common among patients with alcohol abuse disorder (32%),² chronic fatigue syndrome (92%), fibromyalgia (77%), or temporomandibular joint syndrome (64%).³ Seventy percent of patients with IBS are women.⁴ Chronic pelvic pain, dyspareunia, dysmenorrhea, or a history of abdominal surgeries are risk factors for IBS in women.

LINK BETWEEN IBS AND MENTAL ILLNESS

Although mental illness often coexists with IBS, no cause-effect relationship has been shown.⁵

IBS is often preceded by stressful life events, such as family death or divorce,³ and some believe IBS is a precursor to numerous psychiatric disorders. Generalized anxiety disorder, major depression, panic disorder, social phobia, somatization disorder, or dysthymia have been diagnosed in most IBS patients.²

CASE 1: IBS AND DEPRESSION

Ms. R, age 55, has had IBS for 10 years. She has occasional diarrhea and abdominal cramps relieved by bowel movements. She is taking a bulking agent but still sometimes suffers abdominal pain.

She is referred to a psychiatrist after complaining of fatigue, loss of interest in hobbies, and crying spells for 2 months. She denies suicidal ideations. Her referring physician reports that she is taking conjugated estrogens to manage menopause symptoms. She denies any recent stressful life events. Thyroid function, glucose, and CBC are normal.

The challenge: Deciding which to treat first—the IBS symptoms or the depression—and how.

Discussion: The predominant symptom (in Ms. R’s case, abdominal pain) can help determine choice of medication. Bulk-forming agents, antispasmodics, barbiturates, benzodiazepines, and serotonin reuptake inhibitors have historically been used to treat IBS,⁶ but scant evidence supports their use.

Obtaining a thorough prescription history from the primary care physician, OB/GYN, and other treatment team members is critical before formulating a treatment plan. Ms. R’s estrogen use will not affect the choice of psychotropic or IBS medication because there are no significant interactions between estrogen and these classes of drugs.

Ms. R’s abdominal pain and depression can be treated simultaneously. Randomized, controlled trials have demonstrated that tricyclic antidepressants reduce abdominal pain and that behavioral therapy (relaxation therapy, hypnotherapy, and cognitive-behavioral therapy) may relieve individual IBS symptoms.⁷

Case 1 concluded: After reviewing Ms. R’s medications, the psychiatrist starts:

• desipramine, 50 mg at bedtime, to minimize anticholinergic side effects
• and short-term psychotherapy, which helped her identify support mechanisms and ways to better balance her life stresses.

After 6 weeks, her Beck Depression Inventory score improved from 30 at baseline to 8. She reports her abdominal pain is “the best it has been in 10 years.” Six months after diagnosis, she continues to take desipramine and is doing well.

CASE 2: IBS, DEPRESSION, AND PSYCHOSIS

Ms. H, age 32, is referred to a psychiatrist for treatment of depression with paranoid features.

Four years ago, a gastroenterologist diagnosed her as having IBS. She experiences frequent diarrhea and lower abdominal cramping. For 2 years she has been taking the antimuscarinic dicyclomine, 10 mg tid, which has provided some relief from her cramps. An estimated 20 diarrhea attacks per day leaves her housebound much of the time, however.

She reports fatigue, loss of interest in hobbies across 2 months, and paranoid thinking. She denies hallucinations or delusions but believes that her teenage children are discussing her “sickness” and plotting to “drive her crazy.” She is not suicidal.

The challenge: Treating Ms. H’s depression and paranoia while avoiding drug-drug interactions.

Discussion: Adverse drug-drug interactions can occur when prescribing psychotropics to patients with IBS (Table 1). Additive constipation, diarrhea, abdominal pain, and sedation are common interactions between psychotropics and the 5-HT3 antagonists and 5HT4 agonists commonly prescribed for IBS.

Table 1

Interactions between psychotropics and agents prescribed for IBS

	Antispasmodics	Benzodiazepines	SSRIs	Tricyclics
MAOIs	Additive sedation	Additive dizziness, sedation, dry mouth,	Contraindicated–hyperpyrexia and severe neurologic effects	Contraindicated–hyperpyrexia, seizures, and death
SSRIs	Additive sedation	Additive sedation	—-	Increased tricyclic levels with concurrent use
Tricyclics	Additive sedation, dry mouth	Additive sedation	Additive sedation, dry mouth, increased tricyclic levels	—-
Anticonvulsants	Additive sedation	Additive sedation	Increased levels of anticonvulsants	Additive sedation, dry mouth, constipation
Benzodiazepines	Additive sedation	—-	Additive sedation and dry mouth	Additive sedation
Buspirone	Additive sedation, dizziness	Additive sedation	Additive sedation, dizziness, nausea	Additive sedation, dry mouth, constipation, increased tricyclic level
Traditional antipsychotics	Additive sedation, CNS effects	Additive sedation, CNS effects	Additive sedation, dizziness	Additive sedation and anticholinergic effects; increased tricyclic level
Atypical antipsychotics	Additive sedation, CNS effects	Contraindicated–respiratory and cardiovascular collapse	Elevated antipsychotic levels	Levels of both drugs increased
Aripiprazole	Somnolence,constipation	Additive sedation	Increased blood levels of aripiprazole	Increased sedation and anticholinergic effects
Psychotropics and 5-HT3 antagonists taken concomitantly typically lead to additive constipation and abdominal pain.
Psychotropics and 5-HT4 agonists taken concomitantly typically lead to additive diarrhea and/or abdominal pain.
Source: Physician’s Desk Reference. Mobile PDR release version 32. Database version 437. Montvale, NJ: Thomson Healthcare 2003.

 

Box

Other than fiber supplements, most traditional IBS medications are sedating and are associated with anticholinergic side effects. In Ms. H’s case, extreme caution is necessary before prescribing an antidepressant or antipsychotic because of dicyclomine’s additive sedating effects.

Case 2 concluded: After a thorough initial patient interview, the psychiatrist elects to treat Ms. H’s major depression with an antidepressant but delays the use of an antipsychotic to avoid additive sedation.

After talking with Ms. H’s family physician, the psychiatrist stops her dicyclomine and starts sertraline, 100 mg/d. She tolerates the sertraline well and the dosage is titrated across 1 month to 200 mg/d.

Four weeks later, Ms. H’s Beck Depression Inventory score has improved from 26 at baseline to 5, but her paranoid thoughts and frequent diarrhea persist. The psychiatrist adds low-dose olanzapine (5 mg at bedtime) to minimize extrapyramidal side effects. One month later, her depression and paranoia have resolved.

Ms. H’s gastroenterologist instructs her to begin taking alosetron, 1 mg bid, for her continued frequent diarrhea. Adding this agent to her sertraline/olanzapine regimen can lead to additive constipation and abdominal pain, so the psychiatrist monitors her psychiatric medications. One month later, she reports that her affect is much improved and her diarrhea is “gone.”

CASE 3: DEPRESSION AND ABDOMINAL PAIN

Mr. J, age 52, has had depression for 1 year. His depressive symptoms have improved significantly on fluoxetine, 20 mg/d; he once again enjoys life and has a more positive outlook.

The patient was in reasonably good health until about 1 month ago, when he began to experience abdominal pain. He has lost 14 lbs over the past month. He is not taking other medications.

The challenge: Find the cause of Mr. J’s persistent abdominal pain without undermining depression therapy.

Discussion: Although Mr. J’s symptoms might be side effects of fluoxetine, his abdominal pain and weight loss >10 lbs within 1 month are cause for concern. The American College of Gastroenterology has identified six alarm symptoms that could point to a serious medical problem in patients with severe abdominal pain (Box).⁷

Patients who exhibit any of these symptoms should be referred for endoscopic and stool studies. Colon cancer screening should be considered for all patients age 50 and older.

Patients with IBS usually present first to their primary care physicians with abdominal pain and altered bowel habits. These symptoms can occur in many gastrointestinal and systemic illnesses (Table 2).⁸

Table 2

Diagnosing irritable bowel syndrome: What to rule out

Differential diagnosis	Examples
Inflammatory bowel disease	Crohn’s disease, ulcerative colitis
Medication effects	Laxatives, constipating agents
Infections	Parasitic, bacterial, viral, opportunistic
Malabsorption syndromes	Celiac disease, pancreatic insufficiency
Endocrine disorders	Hypothyroidism, hyperthyroidism, diabetes, Addison’s disease
Endocrine tumors (extremely uncommon)	Gastrinoma, carcinoid
Colorectal carcinoma	Adenocarcinoma, villous adenoma
Intestinal pseudo-obstruction	Diabetes, scleroderma
Lactose intolerance	—-
Psychiatric disorders	Depression, anxiety, somatization disorders
Source: Dalton CB, Drossman D. Am Fam Physician. 1997;55(3):875-80.

Case 3 concluded: The psychiatrist and primary care physician consult a gastroenterologist, who performs a colonoscopy and identifies a resectable Duke’s Class B adenocarcinoma in the transverse colon. A partial colectomy is performed.

Three years later, Mr. J is cancer-free and his depression is stable. The psychiatrist advises him to keep taking fluoxetine, 20 mg/d, because the stress of his cancer therapy increases the risk of depression recurrence.

Related resources

• National Institute of Diabetes and Digestive and Kidney Diseases —Irritable Bowel Syndrome www.niddk.nih.gov/health/digest/pubs/irrbowel/irrbowel.htm

Drug brand names

• Alosetron • Lotronex
• Aripiprazole • Abilify
• Buspirone • BuSpar
• Desipramine • Norpramin
• Dicyclomine • Bentyl
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Sertraline • Zoloft

Disclosure

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

In patients with psychotic symptoms, why are African-Americans more likely than whites to be diagnosed with schizophrenia? After more than 30 years of debate, some answers—and remedies for the problem—are becoming clear.

In psychiatry, where interpersonal interactions are key to eliciting diagnostic symptoms and signs, there is an intrinsic risk of misinterpretation when clinician and patient are of different cultural, ethnic, or socioeconomic backgrounds. This article analyzes four factors that contribute to misinterpretation and to ethnic misdiagnosis of schizophrenia. Culturally sensitive strategies are offered to avoid diagnostic bias in clinical practice.

SCHIZOPHRENIA MISDIAGNOSIS

Large epidemiologic studies report similar rates of schizophrenia and bipolar disorder in African-American and white populations.¹ Although patients of both races have been wrongly diagnosed with schizophrenia, the pattern is stronger and more persistent in African-Americans.

Box 1

In the 1970s, Simon et al² studied 192 hospitalized patients, of whom all African-Americans and 85% of whites had been identified clinically as having schizophrenia. Using a structured interview, the researchers found that only 40% of the African Americans and 50% of the whites met diagnostic criteria for schizophrenia. African-Americans with mood disorders were found to be at particular risk of schizophrenia misdiagnosis.

In the 1980s, among 76 patients with a clinical diagnosis of schizophrenia, Mukherjee et al³ diagnosed one-half (52%) with bipolar disorder using a structured clinical interview. Schizophrenia misdiagnoses were more common in African-Americans (86%) and Hispanics (83%) than in whites (51%). In particular, African-Americans were most likely to be misdiagnosed with paranoid schizophrenia. African-Americans complained more commonly than whites of auditory hallucinations, which may represent an ethnic difference in symptomatic presentation of psychotic mood disorders.

In the 1990s, colleagues and I conducted two studies—one of 173 patients in a Tennessee psychiatric hospital⁴ and the other of 490 patients in an Ohio psychiatric emergency service⁵—and found yet again that African-Americans were more likely than whites to be diagnosed with schizophrenia. In the hospital study, higher rates of schizophrenia diagnosis were associated with lower rates of mood disorder diagnosis. This inverse relationship implied that African-Americans with mood disorders were being misdiagnosed with schizophrenia.

Men were more likely than women to be diagnosed with schizophrenia, suggesting that African-American men were most likely to be misdiagnosed. When adjustments were made for gender, black women were found to be at higher risk for misdiagnosis than white women.

Lawson et al⁶ extended this research in a population-based study of African-Americans living in Tennessee. They found that African-Americans constituted 16% of the state’s population but 48% of psychiatric inpatients diagnosed with schizophrenia and 37% of psychiatric outpatients.

CONSEQUENCES OF INACCURATE DIAGNOSIS

Differentiating between schizophrenia (Box 1) and a psychotic mood disorder (Box 2) is more than a semantic exercise. Schizophrenia implies a chronic, unremitting, debilitating illness that worsens over time. Though this perception of schizophrenia is not entirely accurate, in clinical practice its diagnosis imparts a bleak prognosis that may lower the clinician’s expectations for the patient.⁷

Schizophrenia misdiagnosis also may lead the psychiatrist to rely excessively on antipsychotics, rather than attempting thymoleptic and psychotherapy trials. Studies suggest that African-American patients are more likely than similar white patients to receive antipsychotics^4,8,9 and less likely to receive psychotherapy.^5,10

Reasons why African-Americans are often misdiagnosed with schizophrenia remain unclear but probably include four contributing factors:

• differences in symptom presentation compared with whites
• failure by clinicians to identify affective symptoms in African-Americans
• minority patients’ wariness when dealing with health services
• and racial stereotyping.

DIFFERENCES IN SYMPTOM EXPRESSION

African-American patients with mood disorders or schizophrenia are more likely than are similar white patients to complain of auditory hallucinations.^11-13 For example, Strakowski et al¹⁴ examined 330 patients with nonaffective and psychotic diagnoses in a study that was used to develop DSM-IV criteria for schizophrenia. Auditory hallucinations were rated as more severe in African-American than in similar white patients.

 

Box 2

African-American patients also are more likely than whites to exhibit so-called Schneiderian first-rank symptoms of schizophrenia,¹⁵ including:

• delusions of thought broadcasting or insertion
• auditory hallucinations of voices conversing about the patient in the third person.

These symptoms were once used to diagnose schizophrenia, but their lack of specificity has been well documented.^2,16 First-rank symptoms of schizophrenia depend on the specific form of the hallucination or delusion, are likely to be influenced by a patient’s culture, and may be misleading in multicultural populations. Though first-rank symptoms now occupy a minor role in U.S. diagnostic systems, they might continue to sway clinicians—even when using structured diagnostic interviews—to inappropriately diagnose schizophrenia in lieu of affective disorders in minority patients.¹⁵

To extend this finding, our group¹⁶ studied rates and severity of affective and psychotic symptoms—particularly first-rank symptoms—in 100 patients with psychotic mania who met DSM-III-R criteria for bipolar disorder (80%) or schizoaffective disorder, bipolar type (20%) as determined by structured diagnostic interview. No differences in affective symptoms between African-American and white patients were seen. African-Americans were more likely to endorse auditory hallucinations and to report severe auditory hallucinations of voices commenting on their behavior—the only first-rank symptom on which they differed from whites.

Though their affective symptoms were similar, African-Americans were significantly more likely than whites to have been diagnosed with a schizophrenia-spectrum disorder. Because misdiagnosis of African-Americans could not be explained by psychotic symptoms—which were as severe as those of white patients—these findings suggest other mechanisms were at work.

UNIDENTIFIED AFFECTIVE SYMPTOMS

Underidentification of mood disorders in African-American patients may also lead to over-diagnosis of schizophrenia. In a sample of 99 patients, colleagues and I¹⁷ compared clinical diagnoses made in a psychiatric emergency service with those by research investigators using a structured clinical interview. Reasons for diagnostic differences were identified and divided into two categories:

• the same symptoms were recorded but applied differently to diagnostic criteria (criterion variance)
• different information was recorded, which led to diagnostic discrepancies (information variance).

Differences occurred significantly more often in African-American than in white patients, but only information variance was associated with ethnicity. This suggests that clinicians are less likely to elicit appropriate information from African-American than from white psychiatric patients. The fact that researchers obtained this information during diagnostic interviews suggests that the patients could provide it when given appropriate prompts. Specifically, affective symptoms were less likely to be elicited by clinicians than by researchers.

PATIENT WARINESS

Minority patients, when interacting with clinicians of the majority population, may project “protective wariness.”¹⁸ Specific behaviors include hesitancy or reluctance to fully engage with the care provider as a precaution against being exploited or harmed. Cultural misunderstandings¹⁹ and patient concerns about past reports of minorities receiving substandard or unethical health care²⁰ may contribute to this behavior.

Whaley²¹ compared nonpathologic distrust and paranoia in 404 community-living African-Americans and whites. Some were healthy, and some had diagnoses of schizophrenia or depression. African-Americans—particularly those with psychiatric disorders—showed higher levels of distrust than whites. Distrust was also associated with depression in African-Americans but not in whites. Whaley concluded that:

• depressed African-Americans may exhibit more distrust toward clinicians than do whites
• this distrust puts African-Americans at risk of being perceived as paranoid and being misdiagnosed with paranoid schizophrenia.

Table

Remedial actions to avoid ethnic bias in diagnosing schizophrenia

Problem	Remedies
Failure to recognize differences in symptom expression	Become familiar with ethnic differences in how patients describe symptoms Incorporate structured interviews or rating scales into the clinical assessment
Failure to elicit affective symptoms	Incorporate structured interviews or rating scales into the clinical assessment Maintain a high index of suspicion for affective symptoms (see Box 2)
Misinterpreted protective wariness	Clarify the patient’s degree of suspicion; consider this in the historical context of abuses toward minorities by majority populations Become familiar with ethnic differences in how symptoms are described
Covert and overt stereotyping and cultural insensitivity	Review practice patterns Consult with culturally sensitive clinicians as necessary

 

Though Whaley did not report differences in distrust between African-American men and women, others have noted that distrust of health providers may be more common in minority men.¹⁸

RACIAL STEREOTYPING

Compared with similar white men, African-American men with mental disorders are more likely to be:

• referred for mental health care through social and legal—rather than medical—systems and to be involuntarily committed
• perceived as violent—even though controlled research suggests they are not. This misperception can lead to excessive medication and restraints.²²

Differential treatment of African-American men may create a cycle of distrust, hostility, and additional inappropriate treatment. Together, these factors may increase the risk that African-American men will be misdiagnosed with schizophrenia.

Past racism in biomedical and psychiatric practice and research has been documented^23,24 and more recently reviewed by Lawson.¹⁹ Historically, African-Americans were perceived to have a “primitive psychic” nature that was thought to be more susceptible to schizophrenia than depression.¹⁹ Whether these or similar racist stereotypes continue to inject ethnic bias into clinical assessment requires further study.

WHERE DO WE GO FROM HERE?

Although research into methods to eliminate ethnicity bias is sparse, the work reviewed in this article suggests ways that psychiatrists can minimize this problem (Table).

Obtain comprehensive information. Use structured interviews, such as the Structured Clinical Interview for DSM-IV (SCID), and rating scales, such as the Hamilton Depression Scale, which require clinicians to ask about all types of symptoms, particularly affective symptoms.

Review treatment records. Review your practice patterns for evidence of schizophrenia over-diagnosis in African-Americans or other ethnic groups. Examine ethnic differences in legal referrals or use of restraints or seclusion, which may indicate an ethnic bias in how threats are perceived. Only by being aware of bias can one correct it.

Become familiar with cultural and ethnic differences in idioms of distress. Specifically, review research in cultural psychiatry to identify potential differences among cultural groups in how they describe psychiatric symptoms. Talk with colleagues or friends from other cultural groups, and read literature from different ethnic perspectives to increase your cultural sensitivity.

Consult with psychiatrists with expertise in cultural variability of clinical presentation when the diagnosis or threat assessment seems unclear. Consultation is recommended if a patient’s diagnosis is uncertain or if you detect bias in your practice.

These interventions require clinicians to become familiar with psychosocial differences in how patients of various cultural and ethnic groups express psychiatric symptoms. With this understanding, we can better engage wary patients, obtain valid information, and improve clinical practice and patient outcomes.

Finally, psychiatry’s diagnostic systems need to continually address how patient assessment is influenced by ethnicity, culture, gender, and other socio-demographic factors. Studies are needed to examine the contributions of multiple factors—such as symptom differences and stereotyping—that contribute to ethnic-related diagnostic disparities.

Related resources

• Paul AM. Painting insanity black: Why are there more black schizophrenics? Salon.com Dec. 1, 1999. http://www.salon.com/books/it/1999/12/01/schizo/index.html
• Alarcon RD, Westermeyer J, Foulks EF, Ruiz P. Clinical relevance of contemporary cultural psychiatry. J Nerv Ment Dis 1999;187: 465-71.
• Williams DR, Neighbors HW, Jackson JS. Racial/ethnic discrimination and health: findings from community studies. Am J Public Health 2003;93:200-8.
• Lin KM, Smith MW, Ortiz V. Culture and psychopharmacology. Psychiatr Clin North Am 2001; 24:523-38.

Acknowledgement

Preparation of this manuscript was supported in part by National Institutes of Health grant MH56352.

In patients with psychotic symptoms, why are African-Americans more likely than whites to be diagnosed with schizophrenia? After more than 30 years of debate, some answers—and remedies for the problem—are becoming clear.

In psychiatry, where interpersonal interactions are key to eliciting diagnostic symptoms and signs, there is an intrinsic risk of misinterpretation when clinician and patient are of different cultural, ethnic, or socioeconomic backgrounds. This article analyzes four factors that contribute to misinterpretation and to ethnic misdiagnosis of schizophrenia. Culturally sensitive strategies are offered to avoid diagnostic bias in clinical practice.

SCHIZOPHRENIA MISDIAGNOSIS

Large epidemiologic studies report similar rates of schizophrenia and bipolar disorder in African-American and white populations.¹ Although patients of both races have been wrongly diagnosed with schizophrenia, the pattern is stronger and more persistent in African-Americans.

Box 1

In the 1970s, Simon et al² studied 192 hospitalized patients, of whom all African-Americans and 85% of whites had been identified clinically as having schizophrenia. Using a structured interview, the researchers found that only 40% of the African Americans and 50% of the whites met diagnostic criteria for schizophrenia. African-Americans with mood disorders were found to be at particular risk of schizophrenia misdiagnosis.

In the 1980s, among 76 patients with a clinical diagnosis of schizophrenia, Mukherjee et al³ diagnosed one-half (52%) with bipolar disorder using a structured clinical interview. Schizophrenia misdiagnoses were more common in African-Americans (86%) and Hispanics (83%) than in whites (51%). In particular, African-Americans were most likely to be misdiagnosed with paranoid schizophrenia. African-Americans complained more commonly than whites of auditory hallucinations, which may represent an ethnic difference in symptomatic presentation of psychotic mood disorders.

In the 1990s, colleagues and I conducted two studies—one of 173 patients in a Tennessee psychiatric hospital⁴ and the other of 490 patients in an Ohio psychiatric emergency service⁵—and found yet again that African-Americans were more likely than whites to be diagnosed with schizophrenia. In the hospital study, higher rates of schizophrenia diagnosis were associated with lower rates of mood disorder diagnosis. This inverse relationship implied that African-Americans with mood disorders were being misdiagnosed with schizophrenia.

Men were more likely than women to be diagnosed with schizophrenia, suggesting that African-American men were most likely to be misdiagnosed. When adjustments were made for gender, black women were found to be at higher risk for misdiagnosis than white women.

Lawson et al⁶ extended this research in a population-based study of African-Americans living in Tennessee. They found that African-Americans constituted 16% of the state’s population but 48% of psychiatric inpatients diagnosed with schizophrenia and 37% of psychiatric outpatients.

CONSEQUENCES OF INACCURATE DIAGNOSIS

Differentiating between schizophrenia (Box 1) and a psychotic mood disorder (Box 2) is more than a semantic exercise. Schizophrenia implies a chronic, unremitting, debilitating illness that worsens over time. Though this perception of schizophrenia is not entirely accurate, in clinical practice its diagnosis imparts a bleak prognosis that may lower the clinician’s expectations for the patient.⁷

Schizophrenia misdiagnosis also may lead the psychiatrist to rely excessively on antipsychotics, rather than attempting thymoleptic and psychotherapy trials. Studies suggest that African-American patients are more likely than similar white patients to receive antipsychotics^4,8,9 and less likely to receive psychotherapy.^5,10

Reasons why African-Americans are often misdiagnosed with schizophrenia remain unclear but probably include four contributing factors:

• differences in symptom presentation compared with whites
• failure by clinicians to identify affective symptoms in African-Americans
• minority patients’ wariness when dealing with health services
• and racial stereotyping.

DIFFERENCES IN SYMPTOM EXPRESSION

African-American patients with mood disorders or schizophrenia are more likely than are similar white patients to complain of auditory hallucinations.^11-13 For example, Strakowski et al¹⁴ examined 330 patients with nonaffective and psychotic diagnoses in a study that was used to develop DSM-IV criteria for schizophrenia. Auditory hallucinations were rated as more severe in African-American than in similar white patients.

 

Box 2

African-American patients also are more likely than whites to exhibit so-called Schneiderian first-rank symptoms of schizophrenia,¹⁵ including:

• delusions of thought broadcasting or insertion
• auditory hallucinations of voices conversing about the patient in the third person.

These symptoms were once used to diagnose schizophrenia, but their lack of specificity has been well documented.^2,16 First-rank symptoms of schizophrenia depend on the specific form of the hallucination or delusion, are likely to be influenced by a patient’s culture, and may be misleading in multicultural populations. Though first-rank symptoms now occupy a minor role in U.S. diagnostic systems, they might continue to sway clinicians—even when using structured diagnostic interviews—to inappropriately diagnose schizophrenia in lieu of affective disorders in minority patients.¹⁵

To extend this finding, our group¹⁶ studied rates and severity of affective and psychotic symptoms—particularly first-rank symptoms—in 100 patients with psychotic mania who met DSM-III-R criteria for bipolar disorder (80%) or schizoaffective disorder, bipolar type (20%) as determined by structured diagnostic interview. No differences in affective symptoms between African-American and white patients were seen. African-Americans were more likely to endorse auditory hallucinations and to report severe auditory hallucinations of voices commenting on their behavior—the only first-rank symptom on which they differed from whites.

Though their affective symptoms were similar, African-Americans were significantly more likely than whites to have been diagnosed with a schizophrenia-spectrum disorder. Because misdiagnosis of African-Americans could not be explained by psychotic symptoms—which were as severe as those of white patients—these findings suggest other mechanisms were at work.

UNIDENTIFIED AFFECTIVE SYMPTOMS

Underidentification of mood disorders in African-American patients may also lead to over-diagnosis of schizophrenia. In a sample of 99 patients, colleagues and I¹⁷ compared clinical diagnoses made in a psychiatric emergency service with those by research investigators using a structured clinical interview. Reasons for diagnostic differences were identified and divided into two categories:

• the same symptoms were recorded but applied differently to diagnostic criteria (criterion variance)
• different information was recorded, which led to diagnostic discrepancies (information variance).

Differences occurred significantly more often in African-American than in white patients, but only information variance was associated with ethnicity. This suggests that clinicians are less likely to elicit appropriate information from African-American than from white psychiatric patients. The fact that researchers obtained this information during diagnostic interviews suggests that the patients could provide it when given appropriate prompts. Specifically, affective symptoms were less likely to be elicited by clinicians than by researchers.

PATIENT WARINESS

Minority patients, when interacting with clinicians of the majority population, may project “protective wariness.”¹⁸ Specific behaviors include hesitancy or reluctance to fully engage with the care provider as a precaution against being exploited or harmed. Cultural misunderstandings¹⁹ and patient concerns about past reports of minorities receiving substandard or unethical health care²⁰ may contribute to this behavior.

Whaley²¹ compared nonpathologic distrust and paranoia in 404 community-living African-Americans and whites. Some were healthy, and some had diagnoses of schizophrenia or depression. African-Americans—particularly those with psychiatric disorders—showed higher levels of distrust than whites. Distrust was also associated with depression in African-Americans but not in whites. Whaley concluded that:

• depressed African-Americans may exhibit more distrust toward clinicians than do whites
• this distrust puts African-Americans at risk of being perceived as paranoid and being misdiagnosed with paranoid schizophrenia.

Table

Remedial actions to avoid ethnic bias in diagnosing schizophrenia

Problem	Remedies
Failure to recognize differences in symptom expression	Become familiar with ethnic differences in how patients describe symptoms Incorporate structured interviews or rating scales into the clinical assessment
Failure to elicit affective symptoms	Incorporate structured interviews or rating scales into the clinical assessment Maintain a high index of suspicion for affective symptoms (see Box 2)
Misinterpreted protective wariness	Clarify the patient’s degree of suspicion; consider this in the historical context of abuses toward minorities by majority populations Become familiar with ethnic differences in how symptoms are described
Covert and overt stereotyping and cultural insensitivity	Review practice patterns Consult with culturally sensitive clinicians as necessary

 

Though Whaley did not report differences in distrust between African-American men and women, others have noted that distrust of health providers may be more common in minority men.¹⁸

RACIAL STEREOTYPING

Compared with similar white men, African-American men with mental disorders are more likely to be:

• referred for mental health care through social and legal—rather than medical—systems and to be involuntarily committed
• perceived as violent—even though controlled research suggests they are not. This misperception can lead to excessive medication and restraints.²²

Differential treatment of African-American men may create a cycle of distrust, hostility, and additional inappropriate treatment. Together, these factors may increase the risk that African-American men will be misdiagnosed with schizophrenia.

Past racism in biomedical and psychiatric practice and research has been documented^23,24 and more recently reviewed by Lawson.¹⁹ Historically, African-Americans were perceived to have a “primitive psychic” nature that was thought to be more susceptible to schizophrenia than depression.¹⁹ Whether these or similar racist stereotypes continue to inject ethnic bias into clinical assessment requires further study.

WHERE DO WE GO FROM HERE?

Although research into methods to eliminate ethnicity bias is sparse, the work reviewed in this article suggests ways that psychiatrists can minimize this problem (Table).

Obtain comprehensive information. Use structured interviews, such as the Structured Clinical Interview for DSM-IV (SCID), and rating scales, such as the Hamilton Depression Scale, which require clinicians to ask about all types of symptoms, particularly affective symptoms.

Review treatment records. Review your practice patterns for evidence of schizophrenia over-diagnosis in African-Americans or other ethnic groups. Examine ethnic differences in legal referrals or use of restraints or seclusion, which may indicate an ethnic bias in how threats are perceived. Only by being aware of bias can one correct it.

Become familiar with cultural and ethnic differences in idioms of distress. Specifically, review research in cultural psychiatry to identify potential differences among cultural groups in how they describe psychiatric symptoms. Talk with colleagues or friends from other cultural groups, and read literature from different ethnic perspectives to increase your cultural sensitivity.

Consult with psychiatrists with expertise in cultural variability of clinical presentation when the diagnosis or threat assessment seems unclear. Consultation is recommended if a patient’s diagnosis is uncertain or if you detect bias in your practice.

These interventions require clinicians to become familiar with psychosocial differences in how patients of various cultural and ethnic groups express psychiatric symptoms. With this understanding, we can better engage wary patients, obtain valid information, and improve clinical practice and patient outcomes.

Finally, psychiatry’s diagnostic systems need to continually address how patient assessment is influenced by ethnicity, culture, gender, and other socio-demographic factors. Studies are needed to examine the contributions of multiple factors—such as symptom differences and stereotyping—that contribute to ethnic-related diagnostic disparities.

Related resources

• Paul AM. Painting insanity black: Why are there more black schizophrenics? Salon.com Dec. 1, 1999. http://www.salon.com/books/it/1999/12/01/schizo/index.html
• Alarcon RD, Westermeyer J, Foulks EF, Ruiz P. Clinical relevance of contemporary cultural psychiatry. J Nerv Ment Dis 1999;187: 465-71.
• Williams DR, Neighbors HW, Jackson JS. Racial/ethnic discrimination and health: findings from community studies. Am J Public Health 2003;93:200-8.
• Lin KM, Smith MW, Ortiz V. Culture and psychopharmacology. Psychiatr Clin North Am 2001; 24:523-38.

Acknowledgement

Preparation of this manuscript was supported in part by National Institutes of Health grant MH56352.

In patients with psychotic symptoms, why are African-Americans more likely than whites to be diagnosed with schizophrenia? After more than 30 years of debate, some answers—and remedies for the problem—are becoming clear.

In psychiatry, where interpersonal interactions are key to eliciting diagnostic symptoms and signs, there is an intrinsic risk of misinterpretation when clinician and patient are of different cultural, ethnic, or socioeconomic backgrounds. This article analyzes four factors that contribute to misinterpretation and to ethnic misdiagnosis of schizophrenia. Culturally sensitive strategies are offered to avoid diagnostic bias in clinical practice.

SCHIZOPHRENIA MISDIAGNOSIS

Large epidemiologic studies report similar rates of schizophrenia and bipolar disorder in African-American and white populations.¹ Although patients of both races have been wrongly diagnosed with schizophrenia, the pattern is stronger and more persistent in African-Americans.

Box 1

In the 1970s, Simon et al² studied 192 hospitalized patients, of whom all African-Americans and 85% of whites had been identified clinically as having schizophrenia. Using a structured interview, the researchers found that only 40% of the African Americans and 50% of the whites met diagnostic criteria for schizophrenia. African-Americans with mood disorders were found to be at particular risk of schizophrenia misdiagnosis.

In the 1980s, among 76 patients with a clinical diagnosis of schizophrenia, Mukherjee et al³ diagnosed one-half (52%) with bipolar disorder using a structured clinical interview. Schizophrenia misdiagnoses were more common in African-Americans (86%) and Hispanics (83%) than in whites (51%). In particular, African-Americans were most likely to be misdiagnosed with paranoid schizophrenia. African-Americans complained more commonly than whites of auditory hallucinations, which may represent an ethnic difference in symptomatic presentation of psychotic mood disorders.

In the 1990s, colleagues and I conducted two studies—one of 173 patients in a Tennessee psychiatric hospital⁴ and the other of 490 patients in an Ohio psychiatric emergency service⁵—and found yet again that African-Americans were more likely than whites to be diagnosed with schizophrenia. In the hospital study, higher rates of schizophrenia diagnosis were associated with lower rates of mood disorder diagnosis. This inverse relationship implied that African-Americans with mood disorders were being misdiagnosed with schizophrenia.

Men were more likely than women to be diagnosed with schizophrenia, suggesting that African-American men were most likely to be misdiagnosed. When adjustments were made for gender, black women were found to be at higher risk for misdiagnosis than white women.

Lawson et al⁶ extended this research in a population-based study of African-Americans living in Tennessee. They found that African-Americans constituted 16% of the state’s population but 48% of psychiatric inpatients diagnosed with schizophrenia and 37% of psychiatric outpatients.

CONSEQUENCES OF INACCURATE DIAGNOSIS

Differentiating between schizophrenia (Box 1) and a psychotic mood disorder (Box 2) is more than a semantic exercise. Schizophrenia implies a chronic, unremitting, debilitating illness that worsens over time. Though this perception of schizophrenia is not entirely accurate, in clinical practice its diagnosis imparts a bleak prognosis that may lower the clinician’s expectations for the patient.⁷

Schizophrenia misdiagnosis also may lead the psychiatrist to rely excessively on antipsychotics, rather than attempting thymoleptic and psychotherapy trials. Studies suggest that African-American patients are more likely than similar white patients to receive antipsychotics^4,8,9 and less likely to receive psychotherapy.^5,10

Reasons why African-Americans are often misdiagnosed with schizophrenia remain unclear but probably include four contributing factors:

• differences in symptom presentation compared with whites
• failure by clinicians to identify affective symptoms in African-Americans
• minority patients’ wariness when dealing with health services
• and racial stereotyping.

DIFFERENCES IN SYMPTOM EXPRESSION

African-American patients with mood disorders or schizophrenia are more likely than are similar white patients to complain of auditory hallucinations.^11-13 For example, Strakowski et al¹⁴ examined 330 patients with nonaffective and psychotic diagnoses in a study that was used to develop DSM-IV criteria for schizophrenia. Auditory hallucinations were rated as more severe in African-American than in similar white patients.

 

Box 2

African-American patients also are more likely than whites to exhibit so-called Schneiderian first-rank symptoms of schizophrenia,¹⁵ including:

• delusions of thought broadcasting or insertion
• auditory hallucinations of voices conversing about the patient in the third person.

These symptoms were once used to diagnose schizophrenia, but their lack of specificity has been well documented.^2,16 First-rank symptoms of schizophrenia depend on the specific form of the hallucination or delusion, are likely to be influenced by a patient’s culture, and may be misleading in multicultural populations. Though first-rank symptoms now occupy a minor role in U.S. diagnostic systems, they might continue to sway clinicians—even when using structured diagnostic interviews—to inappropriately diagnose schizophrenia in lieu of affective disorders in minority patients.¹⁵

To extend this finding, our group¹⁶ studied rates and severity of affective and psychotic symptoms—particularly first-rank symptoms—in 100 patients with psychotic mania who met DSM-III-R criteria for bipolar disorder (80%) or schizoaffective disorder, bipolar type (20%) as determined by structured diagnostic interview. No differences in affective symptoms between African-American and white patients were seen. African-Americans were more likely to endorse auditory hallucinations and to report severe auditory hallucinations of voices commenting on their behavior—the only first-rank symptom on which they differed from whites.

Though their affective symptoms were similar, African-Americans were significantly more likely than whites to have been diagnosed with a schizophrenia-spectrum disorder. Because misdiagnosis of African-Americans could not be explained by psychotic symptoms—which were as severe as those of white patients—these findings suggest other mechanisms were at work.

UNIDENTIFIED AFFECTIVE SYMPTOMS

Underidentification of mood disorders in African-American patients may also lead to over-diagnosis of schizophrenia. In a sample of 99 patients, colleagues and I¹⁷ compared clinical diagnoses made in a psychiatric emergency service with those by research investigators using a structured clinical interview. Reasons for diagnostic differences were identified and divided into two categories:

• the same symptoms were recorded but applied differently to diagnostic criteria (criterion variance)
• different information was recorded, which led to diagnostic discrepancies (information variance).

Differences occurred significantly more often in African-American than in white patients, but only information variance was associated with ethnicity. This suggests that clinicians are less likely to elicit appropriate information from African-American than from white psychiatric patients. The fact that researchers obtained this information during diagnostic interviews suggests that the patients could provide it when given appropriate prompts. Specifically, affective symptoms were less likely to be elicited by clinicians than by researchers.

PATIENT WARINESS

Minority patients, when interacting with clinicians of the majority population, may project “protective wariness.”¹⁸ Specific behaviors include hesitancy or reluctance to fully engage with the care provider as a precaution against being exploited or harmed. Cultural misunderstandings¹⁹ and patient concerns about past reports of minorities receiving substandard or unethical health care²⁰ may contribute to this behavior.

Whaley²¹ compared nonpathologic distrust and paranoia in 404 community-living African-Americans and whites. Some were healthy, and some had diagnoses of schizophrenia or depression. African-Americans—particularly those with psychiatric disorders—showed higher levels of distrust than whites. Distrust was also associated with depression in African-Americans but not in whites. Whaley concluded that:

• depressed African-Americans may exhibit more distrust toward clinicians than do whites
• this distrust puts African-Americans at risk of being perceived as paranoid and being misdiagnosed with paranoid schizophrenia.

Table

Remedial actions to avoid ethnic bias in diagnosing schizophrenia

Problem	Remedies
Failure to recognize differences in symptom expression	Become familiar with ethnic differences in how patients describe symptoms Incorporate structured interviews or rating scales into the clinical assessment
Failure to elicit affective symptoms	Incorporate structured interviews or rating scales into the clinical assessment Maintain a high index of suspicion for affective symptoms (see Box 2)
Misinterpreted protective wariness	Clarify the patient’s degree of suspicion; consider this in the historical context of abuses toward minorities by majority populations Become familiar with ethnic differences in how symptoms are described
Covert and overt stereotyping and cultural insensitivity	Review practice patterns Consult with culturally sensitive clinicians as necessary

 

Though Whaley did not report differences in distrust between African-American men and women, others have noted that distrust of health providers may be more common in minority men.¹⁸

RACIAL STEREOTYPING

Compared with similar white men, African-American men with mental disorders are more likely to be:

• referred for mental health care through social and legal—rather than medical—systems and to be involuntarily committed
• perceived as violent—even though controlled research suggests they are not. This misperception can lead to excessive medication and restraints.²²

Differential treatment of African-American men may create a cycle of distrust, hostility, and additional inappropriate treatment. Together, these factors may increase the risk that African-American men will be misdiagnosed with schizophrenia.

Past racism in biomedical and psychiatric practice and research has been documented^23,24 and more recently reviewed by Lawson.¹⁹ Historically, African-Americans were perceived to have a “primitive psychic” nature that was thought to be more susceptible to schizophrenia than depression.¹⁹ Whether these or similar racist stereotypes continue to inject ethnic bias into clinical assessment requires further study.

WHERE DO WE GO FROM HERE?

Although research into methods to eliminate ethnicity bias is sparse, the work reviewed in this article suggests ways that psychiatrists can minimize this problem (Table).

Obtain comprehensive information. Use structured interviews, such as the Structured Clinical Interview for DSM-IV (SCID), and rating scales, such as the Hamilton Depression Scale, which require clinicians to ask about all types of symptoms, particularly affective symptoms.

Review treatment records. Review your practice patterns for evidence of schizophrenia over-diagnosis in African-Americans or other ethnic groups. Examine ethnic differences in legal referrals or use of restraints or seclusion, which may indicate an ethnic bias in how threats are perceived. Only by being aware of bias can one correct it.

Become familiar with cultural and ethnic differences in idioms of distress. Specifically, review research in cultural psychiatry to identify potential differences among cultural groups in how they describe psychiatric symptoms. Talk with colleagues or friends from other cultural groups, and read literature from different ethnic perspectives to increase your cultural sensitivity.

Consult with psychiatrists with expertise in cultural variability of clinical presentation when the diagnosis or threat assessment seems unclear. Consultation is recommended if a patient’s diagnosis is uncertain or if you detect bias in your practice.

These interventions require clinicians to become familiar with psychosocial differences in how patients of various cultural and ethnic groups express psychiatric symptoms. With this understanding, we can better engage wary patients, obtain valid information, and improve clinical practice and patient outcomes.

Finally, psychiatry’s diagnostic systems need to continually address how patient assessment is influenced by ethnicity, culture, gender, and other socio-demographic factors. Studies are needed to examine the contributions of multiple factors—such as symptom differences and stereotyping—that contribute to ethnic-related diagnostic disparities.

Related resources

• Paul AM. Painting insanity black: Why are there more black schizophrenics? Salon.com Dec. 1, 1999. http://www.salon.com/books/it/1999/12/01/schizo/index.html
• Alarcon RD, Westermeyer J, Foulks EF, Ruiz P. Clinical relevance of contemporary cultural psychiatry. J Nerv Ment Dis 1999;187: 465-71.
• Williams DR, Neighbors HW, Jackson JS. Racial/ethnic discrimination and health: findings from community studies. Am J Public Health 2003;93:200-8.
• Lin KM, Smith MW, Ortiz V. Culture and psychopharmacology. Psychiatr Clin North Am 2001; 24:523-38.

Acknowledgement

Preparation of this manuscript was supported in part by National Institutes of Health grant MH56352.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

Sign	Example
Somatic concern	Delusions of fatal illness
Grandiosity	Special relation to God or royalty
Suspiciousness	Delusions of spousal infidelity
Hallucinations	Foul body odor
Unusual thought	Bizarre, confused ideation
Depressive delusion	Worthlessness, guilt, feelings of deserving death or punishment
Source: Based on the Brief Psychiatric Rating Scale.14

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

 

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

We can apply a similar standard when considering ECT in patients first treated with medication.¹⁸ A patient’s depression could be defined as therapy-resistant after an inadequate response to 4-week courses (in either order) of:

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

 

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

Sign	Example
Somatic concern	Delusions of fatal illness
Grandiosity	Special relation to God or royalty
Suspiciousness	Delusions of spousal infidelity
Hallucinations	Foul body odor
Unusual thought	Bizarre, confused ideation
Depressive delusion	Worthlessness, guilt, feelings of deserving death or punishment
Source: Based on the Brief Psychiatric Rating Scale.14

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

 

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

We can apply a similar standard when considering ECT in patients first treated with medication.¹⁸ A patient’s depression could be defined as therapy-resistant after an inadequate response to 4-week courses (in either order) of:

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

 

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

Sign	Example
Somatic concern	Delusions of fatal illness
Grandiosity	Special relation to God or royalty
Suspiciousness	Delusions of spousal infidelity
Hallucinations	Foul body odor
Unusual thought	Bizarre, confused ideation
Depressive delusion	Worthlessness, guilt, feelings of deserving death or punishment
Source: Based on the Brief Psychiatric Rating Scale.14

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

 

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

We can apply a similar standard when considering ECT in patients first treated with medication.¹⁸ A patient’s depression could be defined as therapy-resistant after an inadequate response to 4-week courses (in either order) of:

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

 

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Disorder	Risk of alcohol use disorder (odds ratio)	Source of data (population survey)
Drug use disorder	25.1	NLAES
Mania	5.6	NCS
Major depression	3.7	NLAES
Obsessive-compulsive disorder	3.4	ECA
Generalized anxiety disorder	2.7	NCS
Phobia	2.3	NCS
Posttraumatic stress disorder	2.2	NCS
Panic disorder	1.4	NCS
NLAES: National Longitudinal Alcohol Epidemiological Survey
NCS: National Comorbidity Survey
ECA: Epidemiologic Catchment Area

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

 

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

Marker	Time needed for return to normal limits	Level of drinking characterized	Comments
Gamma glutamyltransferase (GGT)	2 to 6 weeks of abstinence	~70 drinks/wk for several weeks	Most common and reliable of the traditional markers of heavy drinking; many sources of false positives
Aspartate aminotransferase (AST) (formerly SGOT)	7 days, but much variability in declines with abstinence	Unknown, but heavy	Present in many organs; many sources of false positives; moderate correlations with GGT
Alanine aminotransferase (ALT) (formerly SGPT)	Unknown	Unknown, but heavy	Many sources of false positives and less sensitive than AST; ratio of AST to ALT may be more accurate
Macrocytic volume (MCV)	Unknown; half-life ~40 days	Unknown, but regular and heavy	Poor sensitivity and specificity; even with abstinence, very slow return to normal limits and may increase at first; little, if any, gender effect
Carbohydrate-deficient transferrin (CDT)	2 to 4 weeks of abstinence	>60 grams/day for approximately 2 weeks	Few sources of false positives; excellent indicator of relapse

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

 

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

Measure	Strengths	Weaknesses
Self-report	Noninvasive Inexpensive High validity Flexible window of assessment Immediate results	Easily feigned Accuracy depends on patient’s verbal skills and memory
Biochemical	Objective Results may be more compelling to patients than self-reports May reflect organ damage Useful in tracking treatment progress	Window of assessment is limited to recent past Results often not immediately available May be more costly than self-report measures

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Disorder	Risk of alcohol use disorder (odds ratio)	Source of data (population survey)
Drug use disorder	25.1	NLAES
Mania	5.6	NCS
Major depression	3.7	NLAES
Obsessive-compulsive disorder	3.4	ECA
Generalized anxiety disorder	2.7	NCS
Phobia	2.3	NCS
Posttraumatic stress disorder	2.2	NCS
Panic disorder	1.4	NCS
NLAES: National Longitudinal Alcohol Epidemiological Survey
NCS: National Comorbidity Survey
ECA: Epidemiologic Catchment Area

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

 

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

Marker	Time needed for return to normal limits	Level of drinking characterized	Comments
Gamma glutamyltransferase (GGT)	2 to 6 weeks of abstinence	~70 drinks/wk for several weeks	Most common and reliable of the traditional markers of heavy drinking; many sources of false positives
Aspartate aminotransferase (AST) (formerly SGOT)	7 days, but much variability in declines with abstinence	Unknown, but heavy	Present in many organs; many sources of false positives; moderate correlations with GGT
Alanine aminotransferase (ALT) (formerly SGPT)	Unknown	Unknown, but heavy	Many sources of false positives and less sensitive than AST; ratio of AST to ALT may be more accurate
Macrocytic volume (MCV)	Unknown; half-life ~40 days	Unknown, but regular and heavy	Poor sensitivity and specificity; even with abstinence, very slow return to normal limits and may increase at first; little, if any, gender effect
Carbohydrate-deficient transferrin (CDT)	2 to 4 weeks of abstinence	>60 grams/day for approximately 2 weeks	Few sources of false positives; excellent indicator of relapse

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

 

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

Measure	Strengths	Weaknesses
Self-report	Noninvasive Inexpensive High validity Flexible window of assessment Immediate results	Easily feigned Accuracy depends on patient’s verbal skills and memory
Biochemical	Objective Results may be more compelling to patients than self-reports May reflect organ damage Useful in tracking treatment progress	Window of assessment is limited to recent past Results often not immediately available May be more costly than self-report measures

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Disorder	Risk of alcohol use disorder (odds ratio)	Source of data (population survey)
Drug use disorder	25.1	NLAES
Mania	5.6	NCS
Major depression	3.7	NLAES
Obsessive-compulsive disorder	3.4	ECA
Generalized anxiety disorder	2.7	NCS
Phobia	2.3	NCS
Posttraumatic stress disorder	2.2	NCS
Panic disorder	1.4	NCS
NLAES: National Longitudinal Alcohol Epidemiological Survey
NCS: National Comorbidity Survey
ECA: Epidemiologic Catchment Area

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

 

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

Marker	Time needed for return to normal limits	Level of drinking characterized	Comments
Gamma glutamyltransferase (GGT)	2 to 6 weeks of abstinence	~70 drinks/wk for several weeks	Most common and reliable of the traditional markers of heavy drinking; many sources of false positives
Aspartate aminotransferase (AST) (formerly SGOT)	7 days, but much variability in declines with abstinence	Unknown, but heavy	Present in many organs; many sources of false positives; moderate correlations with GGT
Alanine aminotransferase (ALT) (formerly SGPT)	Unknown	Unknown, but heavy	Many sources of false positives and less sensitive than AST; ratio of AST to ALT may be more accurate
Macrocytic volume (MCV)	Unknown; half-life ~40 days	Unknown, but regular and heavy	Poor sensitivity and specificity; even with abstinence, very slow return to normal limits and may increase at first; little, if any, gender effect
Carbohydrate-deficient transferrin (CDT)	2 to 4 weeks of abstinence	>60 grams/day for approximately 2 weeks	Few sources of false positives; excellent indicator of relapse

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

 

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

Measure	Strengths	Weaknesses
Self-report	Noninvasive Inexpensive High validity Flexible window of assessment Immediate results	Easily feigned Accuracy depends on patient’s verbal skills and memory
Biochemical	Objective Results may be more compelling to patients than self-reports May reflect organ damage Useful in tracking treatment progress	Window of assessment is limited to recent past Results often not immediately available May be more costly than self-report measures

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Promptly identifying serotonin syndrome and acting decisively can keep side effects at the mild end of the spectrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents.

This article presents the latest evidence on how to:

• reduce the risk of serotonin syndrome
• recognize its symptoms
• and treat patients with mild to life-threatening symptoms.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behavioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic interactions between drugs that increase serotonin activity.^1,2

Table 1

How to recognize serotonin syndrome

System	Clinical signs and symptoms
Autonomic	Diaphoresis, hyperthermia, hypertension, tachycardia, pupillary dilatation, nausea, diarrhea, shivering
Neuromotor	Hyperreflexia, myoclonus, restlessness, tremor, incoordination, rigidity, clonus, teeth chattering, trismus, seizures
Cognitive-behavioral	Confusion, agitation, anxiety, hypomania, insomnia, hallucinations, headache

The syndrome was first identified in animal studies, followed by case reports in humans. The first review—with suggested diagnostic criteria— was published in 1991.¹

Since then, case reports have described serotonin syndrome with many drug combinations, including nonpsychotropics and illicit drugs. Using an irreversible MAOI with a serotonergic agent is the most toxic reported combination, but any drug or combination that increases serotonin can, in theory, cause serotonin syndrome (Table 2). A clinical scale³ is being developed to define and identify this potentially dangerous state, but no consensus has emerged on diagnostic criteria.

Pathophysiology. Serotonin syndrome’s symptoms and signs appear to result from stimulation of specific central and peripheral serotonin receptors, especially 5HT1a and 5HT2. Others—such as 5HT3 and 5HT4—may also be involved in causing GI symptoms and may affect dopaminergic transmission.

Damaged vascular or pulmonary endothelium, atherosclerosis, hypertension, or hypercholesterolemia may increase the risk for serotonin syndrome. In patients with these common medical conditions, reduced endothelial MAO-A activity or reduced ability to secrete endothelium-derived nitric oxide may diminish the ability to metabolize serotonin.²

POTENTIALLY DANGEROUS COMBINATIONS

MAOIs. Serotonin syndrome has been reported as a result of interactions between MAOIs— including selegiline and reversible MAO-A inhibitors (RIMAs)—and various serotonergic compounds. These reports have included fatalities,⁴ some of which were preceded by severe hyperthermia with complications such as disseminated intravascular coagulation, rhabdomyolysis, and renal failure. Some cases resulted from overdoses, but others did not.

Most disturbingly, some cases occurred after patients had undergone the traditional 2-week washout from the MAOI and then took a serotonergic agent.^5-7 In one instance,⁸ a patient who had discontinued fluoxetine for 6 weeks developed serotonin syndrome after starting tranylcypromine. These cases remind us to be vigilant when switching patients from irreversible MAOIs to serotonergic antidepressants or vice versa—even when recommended wash-out times are observed—and not to combine these agents acutely.

Selegiline is a relatively selective MAO-B inhibitor when used at 5 to 10 mg/d to treat Parkinson’s disease, though it loses MAO-B selectivity when used at higher dosages to treat depression. In a study⁹ of 4,568 patients with Parkinson’s disease who received selegiline (in dosages selective for MAO-B) plus an antidepressant:

• 11 (0.24%) experienced symptoms “possibly” consistent with serotonin syndrome
• 2 others (0.04%) experienced serious serotonin syndrome symptoms.⁹

Serotonin syndrome has been reported when MAO-B-selective doses of selegiline were combined with meperidine¹⁰ and nortriptyline.¹¹ This underscores the need for caution when combining these agents, especially if transdermal selegiline— which would not be MAO-B-selective—becomes available for treating depression.

Moclobemide is a RIMA used in treating depression and anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in the United States, but some patients obtain it elsewhere.

Joffe and Bakish reported on safely combining moclobemide with SSRIs,¹² and a review of MAOIs—including RIMAs—indicated that moclobemide was involved in only 9 of 226 cases of adverse effects and 3 of 105 cases of defined serotonin syndrome.¹³ Most moclobemide-SSRI interactions—including fatalities—involved overdoses in suicide attempts, although toxic symptoms have been reported with clomipramine or meperidine taken at normal dosages.^14,15

In one study,¹⁶ 18 healthy controls received fluoxetine, 20 to 40 mg/d, for 23 days, then were given moclobemide, up to 600 mg/d, or placebo and observed for adverse effects. No indication of serotonin syndrome was observed.

Linezolid is an oxazolidinone antibiotic with relatively weak, nonspecific, but reversible MAO inhibition. Cases of potential serotonin syndrome have been reported with linezolid plus paroxetine¹⁷ or sertraline.¹⁸ Patients in each case were medically ill and taking several other medications, which complicates interpretation of these reports. Nonetheless, physicians should be aware of the potential risk of serotonin syndrome if this antibiotic is combined with serotonergic agents.

 

Table 2

Serotonergic agents and their actions

Actions	Agents
Inhibit serotonin reuptake	Fluoxetine, sertraline, citalopram, escitalopram, paroxetine, clomipramine, venlafaxine, fluvoxamine, tramadol, trazodone, nefazodone, tricyclic antidepressants, amphetamine, cocaine, dextromethorphan, meperidine, St. John’s wort
Increases serotonin synthesis	Tryptophan
Inhibit serotonin metabolism	Phenelzine, tranylcypromine, isocarboxazid, selegiline (deprenyl), linezolid, moclobemide
Increase serotonin release	MDMA (“Ecstasy”), amphetamine, cocaine, fenfluramine
Increase serotonin activity	Lithium, ECT
Serotonin receptor agonists	Buspirone, sumatriptan and other “triptans” used for migraine

Atypical antipsychotics. Original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic prior to the syndrome’s onset.¹ However, serotonin syndrome has been reported with combinations of risperidone with paroxetine,¹⁹ olanzapine with mirtazapine and tramadol,²⁰ and olanzapine with lithium and citalopram.²¹ The 5HT2 antagonist effect of these atypical antipsychotics may have led indirectly to overactivation of 5HT1a receptors and serotonin syndrome. In each case, neuroleptic malignant syndrome was ruled out.

Table 3

Signs and symptoms that differentiate 5 hyperthermic states

Hyperthermic state	Symptoms/signs	Lab findings	Cause
Serotonin syndrome	Typically rapid onset with hyperreflexia, tremors, myoclonus, diaphoresis, confusion, agitation, or shivering; muscular rigidity not invariably present	Nonspecific	Increased serotonergic tone
Neuroleptic malignant syndrome	Variable rapidity of onset; severe muscular rigidity, diaphoresis, delirium, fluctuating blood pressure, tachycardia, extrapyramidal symptoms	Elevated CPK, leukocytosis	Blockade of dopamine receptors or abrupt withdrawal of a dopamine agonist
Lethal catatonia	Muscular rigidity, diaphoresis, delirium, alternating extreme excitement and stupor, tremors, hypertension	Nonspecific	Evidence of pre-existing psychosis (bipolar disorder, schizophrenia)
Anticholinergic toxicity	Hot, dry skin, pupillary dilatation, tachycardia, constipation, urinary retention, confusion, hallucinations, muscular relaxation	Nonspecific	Agents that block central and peripheral muscarinic cholinergic receptors
Malignant hyperthermia	Rapid onset, severe muscular rigidity, ischemia, hypotension	Elevated CPK, potassium, magnesium; DIC; acidosis; rhabdomyolysis	Inherited disorder with onset after exposure to anesthetic agents that block the neuromuscular junction
CPK: creatine phosphokinase
DIC: disseminated intravascular coagulation

Tramadol is an analgesic with opioid and serotonin-reuptake inhibiting properties that is metabolized by the cytochrome P (CYP)-450 isoenzyme 2D6. Serotonin syndrome has been reported from interactions between tramadol and sertraline²² and fluoxetine.²³ Possible causes include SSRI inhibition of CYP 2D6 metabolism of tramadol, tramadol abuse,²³ and multiple coadministered medications.²²

Sumatriptan is one of the selective 5HT1D agonists used in treating migraine. Gardner and Lynd²⁴ concluded that most patients tolerate sumatriptan with SSRIs or lithium. They felt they could not ensure the safety of sumatriptan with MAOIs, however, because sumatriptan elimination depends on hepatic MAO activity.

Among the 5HT1D agonists, using sumatriptan, zolmitriptan, rizatriptan, or almotriptan with an MAOI or within 2 weeks of discontinuing an MAOI is contraindicated. Naratriptan and frovatriptan appear less likely to interact with MAOIs, based on FDA-approved labeling.

MDMA. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is widely used as a recreational drug, especially at crowded dances (“raves”) and with other drugs.²⁵ This illicit amphetamine derivative stimulates the release of serotonin and inhibits its reuptake.

Kaskey reported the rapid onset of serotonin syndrome when a patient taking lithium and phenelzine ingested MDMA.²⁶ Signs and symptoms of serotonin syndrome also may develop when MDMA is used alone, facilitated by the high ambient temperatures on crowded dance floors and the dancers’ relative dehydration.

Fatalities have been blamed on complications including disseminated intravascular coagulation, rhabdomyolysis, and acute hepatic, renal, or cardiac failure.²⁵ Cases are difficult to interpret because of uncertainty about whether the victim ingested MDMA or another agent or combination.

St. John’s wort (Hypericum perforatum) contains numerous constituents, including hypericin and hyperforin, which have been found to inhibit the synaptic uptake of monoamines, including serotonin.²⁷ Which constituents are responsible for its clinical effect is unclear. Adverse effects from monotherapy include GI symptoms, confusion, dry mouth, dizziness, headache, fatigue, allergic skin reactions, photosensitivity, and urinary frequency.²⁷

Several cases of purported serotonin syndrome have been associated with St. John’s wort alone²⁸ or in combination with SSRIs, nefazodone, or fenfluramine.^29,30 GI symptoms and anxiety were the primary complaints and resolved without complications (adjunctive cyproheptadine was prescribed in two cases, though it is not clear that this agent contributed to resolution).

MISCELLANEOUS COMBINATIONS

Antiretroviral therapy. Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy.³¹ In particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

Erythromycin was reported to induce serotonin syndrome in a 12-year-old boy when added to ongoing treatment with sertraline, an effect believed to be secondary to CYP 3A4 inhibition of sertraline metabolism.³²

Mirtazapine was reported to induce serotonin syndrome in an elderly man 8 days after it was added to a regimen he had been taking for several years to treat chronic obstructive pulmonary disease.³³ Serotonin syndrome also developed in a 12-year-old boy with Ewing’s sarcoma when the 5HT3 antagonist ondansetron was added to mirtazapine and morphine³⁴ and in an 11-year-old girl with acute lymphoblastic leukemia when ondansetron was added to fentanyl. Interestingly, another report³⁵ suggested using mirtazapine to treat serotonin syndrome caused by serotonergic antagonist effects.

 

Reports have associated the following combinations with serotonin syndrome, perhaps as the result of pharmacodynamic and/or pharmacokinetic interactions:

• paroxetine plus dextromethorphan and pseudoephedrine
• paroxetine plus nefazodone
• fluoxetine plus clomipramine and buspirone
• fluvoxamine plus buspirone
• fluoxetine plus buspirone
• amitriptyline plus meperidine and venlafaxine
• venlafaxine and dextroamphetamine
• fluoxetine plus clomipramine.

Table 4

Clinical signs that distinguish hyperthermic states

Signs	Possible diagnosis
Prominent muscular rigidity	Neuroleptic malignant syndrome, malignant hyperthermia, catatonia
Myoclonus/hyperreflexia	Serotonin syndrome
Diaphoresis	Serotonin syndrome, neuroleptic malignant syndrome, catatonia
Hot dry skin	Anticholinergic toxicity
Elevated creatine phosphokinase	Neuroleptic malignant syndrome, malignant hyperthermia
Family history of anesthetic-induced hyperthermia	Malignant hyperthermia

HOW TO RECOGNIZE SEROTONIN SYNDROME

Signs and symptoms of serotonin syndrome can overlap with those seen in neuroleptic malignant syndrome, lethal catatonia, malignant hyperthermia, and anticholinergic toxicity (Table 3),^1,36,37 particularly with fever or hyperthermia (>40.5 °C, 105 °F). Fink³⁷ has opined that acute neurotoxic syndromes such as serotonin syndrome and neuroleptic malignant syndrome also meet criteria for catatonia and are therefore subtypes of catatonia. The types of drugs involved and clinical findings can help distinguish the various hyperthermic states (Table 4).

As mentioned above, original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic agent. This exclusion was intended to avoid confusion between serotonin syndrome and neuroleptic malignant syndrome. Co-administering antipsychotic and serotonergic agents requires heightened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES

If a patient develops serotonin syndrome, immediately discontinue the suspected agent(s) and observe carefully. In most cases, serotonin syndrome will resolve within 24 hours.

In mild cases, lorazepam, 1 to 2 mg slow IV push every 30 minutes until excessive sedation develops, may help. In moderate to severe cases, agents that block serotonin’s action are recommended,² including:

• cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours)
• propranolol (1 to 3 mg IV every 5 minutes, up to 0.1 mg/kg).

Case reports attest to these agents’ potential benefit. Other clinicians have reported using mirtazapine,³⁵ nitroglycerin,³⁸ and chlorpromazine.¹

Serotonin syndrome symptoms resolved within minutes when IV nitroglycerin was used in a patient with serotonin syndrome and cardiac ischemia. The authors hypothesized that nitroglycerin, via nitric acid, provided an “off” signal for serotonin, though they did not advocate this as a routine treatment.³⁸

The rationale for using chlorpromazine is its potential to block serotonin receptors. I would avoid the routine use of any antipsychotic agent in this setting, however, to minimize the risk of neuroleptic malignant syndrome.

Severe cases. Intensive care observation and treatment is required for patients with severe serotonin syndrome, including evidence of hyperthermia, DIC, rhabdomyolysis, renal failure, or aspiration. In cases of hyperthermia, supportive measures and standard treatments include muscle relaxants, cooling, and endotracheal intubation.

Severe complications are most likely with interactions between MAOIs and serotonergic agents, especially in overdose. Therefore, using such combinations requires close observation.

Related resources

• Di Rosa AE, Morgante L, Spina E et al. Epidemiology and pathoetiology of neurological syndromes with hyperthermia. Funct Neurol 1995;10:111-19.
• Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypothesis 2000;55: 218-24.
• Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.

Drug brand names

• Almotriptan • Axert
• Amitriptyline • Elavil
• Buspirone • Buspar
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Dextroamphetamine • Dexedrine
• Dextromethorphan • Delsym
• Efavirenz • Sustiva
• Escitalopram • Lexapro
• Fenfluramine • Pondimin
• Fentanyl • Sublimaze
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Isocarboxazid • Marplan
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Moclobemide • Aurorix
• Nortriptyline • Pamelor
• Naratriptan, • Amerge
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Paroxetine • Paxil
• Phenelzine • Nardil
• Propranolol • Inderal
• Risperidone • Risperdal
• Ritonavir • Norvir
• Rizatriptan • Maxalt
• Saquinavir • Invirase
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Sumatriptan • Imitrex
• Tramadol • Ultram
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Zolmitriptan • Zomig

Disclosure

Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson.