Current Psychiatry

Case submitted by: Mary Ann Barnovitz, MD, psychiatry and internal medicine resident in northern California

Psychiatric consultant: Jaesu Han, MD, assistant clinical professor, departments of psychiatry and family medicine, University of California, Davis.

Starting as a regional problem in the southwestern states, methamphetamine abuse has spread to the rest of the country.¹ Commonly known as “ice,” “speed,” “crank,” or “crystal”—to name a few—this synthetically derived stimulant can be used intranasally, swallowed, injected, smoked, or mixed with other drugs.

This case illustrates the type of diagnostic dilemma primary care physicians can see in chronic methamphetamine users. We offer this dialogue to help generalist psychiatrists asked for consultation to unravel the manic, depressive, and substance abuse symptoms that characterize long-term methamphetamine addiction.

Dr. Barnovitz’ patient: Addicted to ‘meth’

Mr. N, age 26, presented at the county outpatient clinic with a history of daily intranasal methamphetamine use. He told me, “I feel like I’m losing my mind and see no reason to go on.” He reported feeling depressed for 7 years and said his primary problem is, “no energy and no hope that things will improve.”

Mr. N complained of decreased concentration, and appetite as well as chronic insomnia. He takes no medications and denies drug allergies. He has no history of tobacco, alcohol, or other illicit drug use. He lives with his ex-girlfriend and has been unemployed for 1 month.

For the past 2 weeks he has been unable to speak slowly, and his thoughts have been “racing too fast to focus.” When I contacted his family (with his permission), they said he is paranoid and persistently claims the FBI is “monitoring his every move.”

Medical history. Mr. N has never been treated for psychiatric conditions. He denies auditory, visual, or tactile hallucinations and has no other medical problems. He has used methamphetamines for 5 years, with no period of sobriety. He said, “I don’t think I have a problem with drugs and see no reason to stop using.” Because of escalating relationship problems with his ex-girlfriend, he reported more-frequent methamphetamine use during the weeks before this assessment.

Physical exam. Mr. N was anxious and hypervigilant, with marked psychomotor agitation. He was otherwise well-related and described his mood as “really down,” with a corresponding labile affect. Vital signs were stable with a pulse of 114 bpm. Neurologic, cardiovascular, pulmonary, and abdominal exam results were normal.

Initial treatment. Despite his depression, I did not think Mr. N warranted psychiatric admission. I started him on paroxetine, 20 mg/d, and referred him for drug rehabilitation.

One week later, Mr. N’s family called me with concerns about his worsening insomnia, depression, paranoid thoughts, and suicidal ideation. I would like help determining if this patient should be admitted for psychiatric evaluation and if symptoms are likely caused by methamphetamine abuse or suggest other psychiatric disorders.

Dr. Han’s consultation

Because of Mr. N’s worsening symptoms and suicidal ideation, I strongly recommend evaluation for inpatient psychiatric hospitalization to allow for methamphetamine detoxification in a safe environment. Ideally, psychotropics would be held and the patient’s mood and psychotic symptoms would improve in a few days, confirming the diagnosis of methamphetamine intoxication.

Acute methamphetamine intoxication (Table 1) is associated with euphoria, talkativeness, and psychomotor agitation that can resemble the manic or mixed phase of bipolar disorder. Methamphetamine withdrawal (Table 2) is associated with dysphoric mood, disturbed sleep, and psychomotor changes that can resemble depression.

Close examination shows Mr. N fulfills criteria for:

• a major depressive episode (feeling depressed for 7 years, decreased energy, decreased concentration, insomnia)
• a manic episode (irritability, pressured speech, racing thoughts, psychomotor agitation, possibly decreased need for sleep).

His contention that the FBI is “monitoring his every move” also introduces a psychotic element.

Mr. N’s presenting diagnosis is amphetamine dependence with a provisional diagnosis of methamphetamine intoxication. Because of ongoing “meth” use, remaining diagnoses to rule out include bipolar disorder, mixed episode with psychotic features, and severe major depression with psychotic features. The drug-induced changes could also be aggravating a primary mood disorder. Obtaining a urine toxicology screen would help document recent intoxication.

Table 1

Symptoms of amphetamine intoxication

Table 2

Symptoms of amphetamine withdrawal

Addressing addiction. Diagnostic uncertainty because of continued methamphetamine use makes pharmacologic treatment of mood symptoms problematic. Mr. N’s denial of a drug problem complicates the physician’s job; nevertheless explaining to him how methamphetamine use can contribute to his symptoms is essential. Motivational interviewing (Box)^2-4 may help you override resistance and motivate behavior change in a patient who is not yet contemplating the need to change.

Keep in mind that methamphetamine use can be linked to other risky behavior such as having multiple sexual partners. Thus, consider screening for sexually transmitted diseases, including HIV.⁵ Likewise, despite patients’ claim of only intranasal methamphetamine use, consider assessing for hepatitis C if the physical exam reveals evidence of intravenous drug use.

Mr. N’s symptoms escalated from depressed to suicidal before these interventions could be tried, however. Short-term goals for him now include safety and detoxification. Long-term goals include diagnosis and treatment of a possible underlying mood disorder and continued abstinence from methamphetamine use.

Box

Deciphering mood disorders. Consider the diagnosis of methamphetamine-induced mood disorder only if symptoms persist or are more severe than would be expected from the pattern of use. Anhedonia and depressed mood usually present in these patients well beyond the typical withdrawal period, but these symptoms persist <1 month. Mr. N’s paranoid symptoms are likely related to methamphetamine intoxication and should resolve within 1 week of detoxification. In some chronic “meth” users, delusions and hallucinations persist for months or even years and are very difficult to distinguish from chronic schizophrenia. These patients require long-term antipsychotic treatment.

Mr. N does not have a substantial period of abstinence from methamphetamine use for us to evaluate symptom resolution. However, we do have a 7-year history of what he calls “depression” and only 5 years of methamphetamine use. This hints that a primary mood disorder existed before substance use, but even here we must be cautious. His description of depression resembles a mixed episode of bipolar disorder, with both manic and depressive elements.

Further exploring early symptoms and family history with Mr. N and his family might suggest major depression or bipolar disorder preceding methamphetamine use.

Comorbid bipolar disorder. If his pre-drug use history suggests bipolar disorder or he continues to show mixed mood symptoms despite sustained abstinence, adding a bipolar diagnosis would be reasonable. For his depressive symptoms, avoid using an antidepressant alone because of the risk of “switching” to mania. All antidepressants can cause switching—paroxetine in Mr. N’s case—but tricyclic antidepressants are most often implicated.

Try a mood stabilizer such as valproate, 20 to 30 mg/kg/d, or olanzapine, 7.5 to 10 mg qhs. After a therapeutic dose is attained, reconsider adding an antidepressant if depressive symptoms still predominate.

Comorbid depression. If, on the other hand, Mr. N’s pre-drug history suggests major depression and he shows essentially depressive symptoms after abstinence, adding a diagnosis of major depression would be reasonable. In that case, retry an antidepressant such as an SSRI.

The sobriety challenge. After Mr. N is discharged from the hospital, continued abstinence from methamphetamines will be a priority, whether his mood disorder was drug-induced or primary.

No specific, well-established treatments exist for methamphetamine dependence. Formal treatment programs use cognitive behavioral therapy, contingency management, and a community reinforcement approach. These techniques have been shown to achieve abstinence and prevent relapse in patients with alcohol, cocaine, and opiate dependence but are not more effective than 12-step community support groups.^6,7

Success with 12-step programs requires at least weekly participation. Daily attendance during early recovery may be particularly helpful for Mr. N, who may have excessive unstructured time during his unemployment. The treatment setting depends on where services are available and the patient’s ability to pay.

Many methamphetamine users relapse within 1 year; thus view drug treatment in the context of a chronic illness rather than a “cure.” A comprehensive approach with continuing treatment and periodic monitoring appointments is essential.

Case submitted by: Mary Ann Barnovitz, MD, psychiatry and internal medicine resident in northern California

Psychiatric consultant: Jaesu Han, MD, assistant clinical professor, departments of psychiatry and family medicine, University of California, Davis.

Starting as a regional problem in the southwestern states, methamphetamine abuse has spread to the rest of the country.¹ Commonly known as “ice,” “speed,” “crank,” or “crystal”—to name a few—this synthetically derived stimulant can be used intranasally, swallowed, injected, smoked, or mixed with other drugs.

This case illustrates the type of diagnostic dilemma primary care physicians can see in chronic methamphetamine users. We offer this dialogue to help generalist psychiatrists asked for consultation to unravel the manic, depressive, and substance abuse symptoms that characterize long-term methamphetamine addiction.

Dr. Barnovitz’ patient: Addicted to ‘meth’

Mr. N, age 26, presented at the county outpatient clinic with a history of daily intranasal methamphetamine use. He told me, “I feel like I’m losing my mind and see no reason to go on.” He reported feeling depressed for 7 years and said his primary problem is, “no energy and no hope that things will improve.”

Mr. N complained of decreased concentration, and appetite as well as chronic insomnia. He takes no medications and denies drug allergies. He has no history of tobacco, alcohol, or other illicit drug use. He lives with his ex-girlfriend and has been unemployed for 1 month.

For the past 2 weeks he has been unable to speak slowly, and his thoughts have been “racing too fast to focus.” When I contacted his family (with his permission), they said he is paranoid and persistently claims the FBI is “monitoring his every move.”

Medical history. Mr. N has never been treated for psychiatric conditions. He denies auditory, visual, or tactile hallucinations and has no other medical problems. He has used methamphetamines for 5 years, with no period of sobriety. He said, “I don’t think I have a problem with drugs and see no reason to stop using.” Because of escalating relationship problems with his ex-girlfriend, he reported more-frequent methamphetamine use during the weeks before this assessment.

Physical exam. Mr. N was anxious and hypervigilant, with marked psychomotor agitation. He was otherwise well-related and described his mood as “really down,” with a corresponding labile affect. Vital signs were stable with a pulse of 114 bpm. Neurologic, cardiovascular, pulmonary, and abdominal exam results were normal.

Initial treatment. Despite his depression, I did not think Mr. N warranted psychiatric admission. I started him on paroxetine, 20 mg/d, and referred him for drug rehabilitation.

One week later, Mr. N’s family called me with concerns about his worsening insomnia, depression, paranoid thoughts, and suicidal ideation. I would like help determining if this patient should be admitted for psychiatric evaluation and if symptoms are likely caused by methamphetamine abuse or suggest other psychiatric disorders.

Dr. Han’s consultation

Because of Mr. N’s worsening symptoms and suicidal ideation, I strongly recommend evaluation for inpatient psychiatric hospitalization to allow for methamphetamine detoxification in a safe environment. Ideally, psychotropics would be held and the patient’s mood and psychotic symptoms would improve in a few days, confirming the diagnosis of methamphetamine intoxication.

Acute methamphetamine intoxication (Table 1) is associated with euphoria, talkativeness, and psychomotor agitation that can resemble the manic or mixed phase of bipolar disorder. Methamphetamine withdrawal (Table 2) is associated with dysphoric mood, disturbed sleep, and psychomotor changes that can resemble depression.

Close examination shows Mr. N fulfills criteria for:

• a major depressive episode (feeling depressed for 7 years, decreased energy, decreased concentration, insomnia)
• a manic episode (irritability, pressured speech, racing thoughts, psychomotor agitation, possibly decreased need for sleep).

His contention that the FBI is “monitoring his every move” also introduces a psychotic element.

Mr. N’s presenting diagnosis is amphetamine dependence with a provisional diagnosis of methamphetamine intoxication. Because of ongoing “meth” use, remaining diagnoses to rule out include bipolar disorder, mixed episode with psychotic features, and severe major depression with psychotic features. The drug-induced changes could also be aggravating a primary mood disorder. Obtaining a urine toxicology screen would help document recent intoxication.

Table 1

Symptoms of amphetamine intoxication

Table 2

Symptoms of amphetamine withdrawal

Addressing addiction. Diagnostic uncertainty because of continued methamphetamine use makes pharmacologic treatment of mood symptoms problematic. Mr. N’s denial of a drug problem complicates the physician’s job; nevertheless explaining to him how methamphetamine use can contribute to his symptoms is essential. Motivational interviewing (Box)^2-4 may help you override resistance and motivate behavior change in a patient who is not yet contemplating the need to change.

Keep in mind that methamphetamine use can be linked to other risky behavior such as having multiple sexual partners. Thus, consider screening for sexually transmitted diseases, including HIV.⁵ Likewise, despite patients’ claim of only intranasal methamphetamine use, consider assessing for hepatitis C if the physical exam reveals evidence of intravenous drug use.

Mr. N’s symptoms escalated from depressed to suicidal before these interventions could be tried, however. Short-term goals for him now include safety and detoxification. Long-term goals include diagnosis and treatment of a possible underlying mood disorder and continued abstinence from methamphetamine use.

Box

Deciphering mood disorders. Consider the diagnosis of methamphetamine-induced mood disorder only if symptoms persist or are more severe than would be expected from the pattern of use. Anhedonia and depressed mood usually present in these patients well beyond the typical withdrawal period, but these symptoms persist <1 month. Mr. N’s paranoid symptoms are likely related to methamphetamine intoxication and should resolve within 1 week of detoxification. In some chronic “meth” users, delusions and hallucinations persist for months or even years and are very difficult to distinguish from chronic schizophrenia. These patients require long-term antipsychotic treatment.

Mr. N does not have a substantial period of abstinence from methamphetamine use for us to evaluate symptom resolution. However, we do have a 7-year history of what he calls “depression” and only 5 years of methamphetamine use. This hints that a primary mood disorder existed before substance use, but even here we must be cautious. His description of depression resembles a mixed episode of bipolar disorder, with both manic and depressive elements.

Further exploring early symptoms and family history with Mr. N and his family might suggest major depression or bipolar disorder preceding methamphetamine use.

Comorbid bipolar disorder. If his pre-drug use history suggests bipolar disorder or he continues to show mixed mood symptoms despite sustained abstinence, adding a bipolar diagnosis would be reasonable. For his depressive symptoms, avoid using an antidepressant alone because of the risk of “switching” to mania. All antidepressants can cause switching—paroxetine in Mr. N’s case—but tricyclic antidepressants are most often implicated.

Try a mood stabilizer such as valproate, 20 to 30 mg/kg/d, or olanzapine, 7.5 to 10 mg qhs. After a therapeutic dose is attained, reconsider adding an antidepressant if depressive symptoms still predominate.

Comorbid depression. If, on the other hand, Mr. N’s pre-drug history suggests major depression and he shows essentially depressive symptoms after abstinence, adding a diagnosis of major depression would be reasonable. In that case, retry an antidepressant such as an SSRI.

The sobriety challenge. After Mr. N is discharged from the hospital, continued abstinence from methamphetamines will be a priority, whether his mood disorder was drug-induced or primary.

No specific, well-established treatments exist for methamphetamine dependence. Formal treatment programs use cognitive behavioral therapy, contingency management, and a community reinforcement approach. These techniques have been shown to achieve abstinence and prevent relapse in patients with alcohol, cocaine, and opiate dependence but are not more effective than 12-step community support groups.^6,7

Success with 12-step programs requires at least weekly participation. Daily attendance during early recovery may be particularly helpful for Mr. N, who may have excessive unstructured time during his unemployment. The treatment setting depends on where services are available and the patient’s ability to pay.

Many methamphetamine users relapse within 1 year; thus view drug treatment in the context of a chronic illness rather than a “cure.” A comprehensive approach with continuing treatment and periodic monitoring appointments is essential.

Case submitted by: Mary Ann Barnovitz, MD, psychiatry and internal medicine resident in northern California

Psychiatric consultant: Jaesu Han, MD, assistant clinical professor, departments of psychiatry and family medicine, University of California, Davis.

Starting as a regional problem in the southwestern states, methamphetamine abuse has spread to the rest of the country.¹ Commonly known as “ice,” “speed,” “crank,” or “crystal”—to name a few—this synthetically derived stimulant can be used intranasally, swallowed, injected, smoked, or mixed with other drugs.

This case illustrates the type of diagnostic dilemma primary care physicians can see in chronic methamphetamine users. We offer this dialogue to help generalist psychiatrists asked for consultation to unravel the manic, depressive, and substance abuse symptoms that characterize long-term methamphetamine addiction.

Dr. Barnovitz’ patient: Addicted to ‘meth’

Mr. N, age 26, presented at the county outpatient clinic with a history of daily intranasal methamphetamine use. He told me, “I feel like I’m losing my mind and see no reason to go on.” He reported feeling depressed for 7 years and said his primary problem is, “no energy and no hope that things will improve.”

Mr. N complained of decreased concentration, and appetite as well as chronic insomnia. He takes no medications and denies drug allergies. He has no history of tobacco, alcohol, or other illicit drug use. He lives with his ex-girlfriend and has been unemployed for 1 month.

For the past 2 weeks he has been unable to speak slowly, and his thoughts have been “racing too fast to focus.” When I contacted his family (with his permission), they said he is paranoid and persistently claims the FBI is “monitoring his every move.”

Medical history. Mr. N has never been treated for psychiatric conditions. He denies auditory, visual, or tactile hallucinations and has no other medical problems. He has used methamphetamines for 5 years, with no period of sobriety. He said, “I don’t think I have a problem with drugs and see no reason to stop using.” Because of escalating relationship problems with his ex-girlfriend, he reported more-frequent methamphetamine use during the weeks before this assessment.

Physical exam. Mr. N was anxious and hypervigilant, with marked psychomotor agitation. He was otherwise well-related and described his mood as “really down,” with a corresponding labile affect. Vital signs were stable with a pulse of 114 bpm. Neurologic, cardiovascular, pulmonary, and abdominal exam results were normal.

Initial treatment. Despite his depression, I did not think Mr. N warranted psychiatric admission. I started him on paroxetine, 20 mg/d, and referred him for drug rehabilitation.

One week later, Mr. N’s family called me with concerns about his worsening insomnia, depression, paranoid thoughts, and suicidal ideation. I would like help determining if this patient should be admitted for psychiatric evaluation and if symptoms are likely caused by methamphetamine abuse or suggest other psychiatric disorders.

Dr. Han’s consultation

Because of Mr. N’s worsening symptoms and suicidal ideation, I strongly recommend evaluation for inpatient psychiatric hospitalization to allow for methamphetamine detoxification in a safe environment. Ideally, psychotropics would be held and the patient’s mood and psychotic symptoms would improve in a few days, confirming the diagnosis of methamphetamine intoxication.

Acute methamphetamine intoxication (Table 1) is associated with euphoria, talkativeness, and psychomotor agitation that can resemble the manic or mixed phase of bipolar disorder. Methamphetamine withdrawal (Table 2) is associated with dysphoric mood, disturbed sleep, and psychomotor changes that can resemble depression.

Close examination shows Mr. N fulfills criteria for:

• a major depressive episode (feeling depressed for 7 years, decreased energy, decreased concentration, insomnia)
• a manic episode (irritability, pressured speech, racing thoughts, psychomotor agitation, possibly decreased need for sleep).

His contention that the FBI is “monitoring his every move” also introduces a psychotic element.

Mr. N’s presenting diagnosis is amphetamine dependence with a provisional diagnosis of methamphetamine intoxication. Because of ongoing “meth” use, remaining diagnoses to rule out include bipolar disorder, mixed episode with psychotic features, and severe major depression with psychotic features. The drug-induced changes could also be aggravating a primary mood disorder. Obtaining a urine toxicology screen would help document recent intoxication.

Table 1

Symptoms of amphetamine intoxication

Table 2

Symptoms of amphetamine withdrawal

Addressing addiction. Diagnostic uncertainty because of continued methamphetamine use makes pharmacologic treatment of mood symptoms problematic. Mr. N’s denial of a drug problem complicates the physician’s job; nevertheless explaining to him how methamphetamine use can contribute to his symptoms is essential. Motivational interviewing (Box)^2-4 may help you override resistance and motivate behavior change in a patient who is not yet contemplating the need to change.

Keep in mind that methamphetamine use can be linked to other risky behavior such as having multiple sexual partners. Thus, consider screening for sexually transmitted diseases, including HIV.⁵ Likewise, despite patients’ claim of only intranasal methamphetamine use, consider assessing for hepatitis C if the physical exam reveals evidence of intravenous drug use.

Mr. N’s symptoms escalated from depressed to suicidal before these interventions could be tried, however. Short-term goals for him now include safety and detoxification. Long-term goals include diagnosis and treatment of a possible underlying mood disorder and continued abstinence from methamphetamine use.

Box

Deciphering mood disorders. Consider the diagnosis of methamphetamine-induced mood disorder only if symptoms persist or are more severe than would be expected from the pattern of use. Anhedonia and depressed mood usually present in these patients well beyond the typical withdrawal period, but these symptoms persist <1 month. Mr. N’s paranoid symptoms are likely related to methamphetamine intoxication and should resolve within 1 week of detoxification. In some chronic “meth” users, delusions and hallucinations persist for months or even years and are very difficult to distinguish from chronic schizophrenia. These patients require long-term antipsychotic treatment.

Mr. N does not have a substantial period of abstinence from methamphetamine use for us to evaluate symptom resolution. However, we do have a 7-year history of what he calls “depression” and only 5 years of methamphetamine use. This hints that a primary mood disorder existed before substance use, but even here we must be cautious. His description of depression resembles a mixed episode of bipolar disorder, with both manic and depressive elements.

Further exploring early symptoms and family history with Mr. N and his family might suggest major depression or bipolar disorder preceding methamphetamine use.

Comorbid bipolar disorder. If his pre-drug use history suggests bipolar disorder or he continues to show mixed mood symptoms despite sustained abstinence, adding a bipolar diagnosis would be reasonable. For his depressive symptoms, avoid using an antidepressant alone because of the risk of “switching” to mania. All antidepressants can cause switching—paroxetine in Mr. N’s case—but tricyclic antidepressants are most often implicated.

Try a mood stabilizer such as valproate, 20 to 30 mg/kg/d, or olanzapine, 7.5 to 10 mg qhs. After a therapeutic dose is attained, reconsider adding an antidepressant if depressive symptoms still predominate.

Comorbid depression. If, on the other hand, Mr. N’s pre-drug history suggests major depression and he shows essentially depressive symptoms after abstinence, adding a diagnosis of major depression would be reasonable. In that case, retry an antidepressant such as an SSRI.

The sobriety challenge. After Mr. N is discharged from the hospital, continued abstinence from methamphetamines will be a priority, whether his mood disorder was drug-induced or primary.

No specific, well-established treatments exist for methamphetamine dependence. Formal treatment programs use cognitive behavioral therapy, contingency management, and a community reinforcement approach. These techniques have been shown to achieve abstinence and prevent relapse in patients with alcohol, cocaine, and opiate dependence but are not more effective than 12-step community support groups.^6,7

Success with 12-step programs requires at least weekly participation. Daily attendance during early recovery may be particularly helpful for Mr. N, who may have excessive unstructured time during his unemployment. The treatment setting depends on where services are available and the patient’s ability to pay.

Many methamphetamine users relapse within 1 year; thus view drug treatment in the context of a chronic illness rather than a “cure.” A comprehensive approach with continuing treatment and periodic monitoring appointments is essential.

Stimulants are most effective for childhood attention-deficit/hyperactivity disorder (ADHD),¹ but they may induce mania or trigger a treatment-resistant course in children with comorbid bipolar disorder. To help you safely manage these complicated symptoms, this article offers a treatment algorithm and tips to:

• differentiate bipolar and ADHD symptoms
• identify patients at risk for stimulantinduced mania
• choose medications by a hierarchythat may reduce the risk of mood destabilization.

Box 1

Adhd and/or bipolar disorder?

Some 70% to 90% of bipolar children and at least 30% to 40% of bipolar adolescents also have ADHD.² This high comorbidity (Box 1)^3-8 might mean that:

• one disorder predisposes to the other
• one is a precursor of the other
• they share common vulnerabilities or causes
• their symptoms overlap so much that patients with one disorder appear to meet criteria for the other.

Some experts contend that bipolar disorder and ADHD usually can be differentiated. Bipolar children score higher than those with ADHD on measures of anxiety/depression, aggression, and attention problems on the Child Behavior Checklist.⁹ Others believe ADHD symptoms that occur with bipolar disorder are a dimension of bipolar illness rather than a separate disorder.¹⁰

For every DSM-IV-TR diagnostic criterion for ADHD, a corresponding diagnostic criterion or common feature of bipolar disorder can be identified (Table 1). Mania and hypomania are obviously associated with hyperactivity and impulsivity, and tangential thinking and distractibility interfere with attention in many patients with bipolar disorder.

Though most ADHD symptoms can occur in bipolar patients, some features of bipolar illness are not characteristic of ADHD (Table 2). Children with ADHD can become hyper-focused on video games and television, for example, but they usually do not become engrossed in long, complicated books or preoccupied with other people, as can occur in bipolar disorder.

Table 1

How ADHD, bipolar symptoms overlap in three domains

Table 2

Bipolar features not seen in ADHD

A treatment hierarchy

Whether a bipolar patient’s attention problems are features of the primary condition or caused by comorbid ADHD may be unclear, but the treatment implications are important. All antidepressants can induce mania/hypomania and increase the risk of mixed states and mood cycling. Because stimulants have antidepressant properties and because some antidepressants are used to treat ADHD, a systematic approach is necessary when treating inattention in juvenile bipolar disorder.

A treatment hierarchy developed by the American Academy of Child and Adolescent Psychiatry Workgroup on Bipolar Disorder recommends beginning psychosocial approaches, such as training parents in behavior management techniques, and:

• treating bipolar disorder first in children who clearly have both ADHD and bipolar disorder
• adding ADHD treatment if ADHD symptoms persist and impair functioning.²

Who’s at risk for mood destabilization?

No data address differences between bipolar patients whose mood disorders deteriorate with stimulant use and those who remain stable. However, risk factors for mood destabilization that have been reported with antidepressants likely also apply to stimulants (Table 3) because stimulants’ adverse effects in bipolar disorder are probably related to their antidepressant properties.

For example, depressed patients who report that an antidepressant worked within hours to days may have bipolar disorder and be at risk for mood destabilization leading to treatment resistance.¹¹ Antidepressant-induced mania also may be more likely:

• when depression is mixed with hypomanic symptoms such as racing thoughts, excessive talkativeness, aggression, irritability, distractibility, and increased drive¹²
• in patients with a history of antidepressant-induced mania, family history of bipolar disorder, or multiple antidepressant trials.¹³

Similarly, patients who report feeling better immediately after starting a stimulant—especially if they have evidence of elation, increased irritability, more aggression or impulsivity, decreased sleep, or related symptoms—may be developing stimulant-induced hypomania.

Table 3

Risk factors that may increase risk of stimulant-induced mania

Antidepressant-induced mania

Most studies of antidepressant-induced mania have examined outright mania, but hypomania and subsyndromal hypomanic syndromes also may cause significant morbidity and may worsen bipolar disorder’s course. A change in polarity may worsen a patient’s prognosis, but how do we know that antidepressants (or stimulants) caused it?

One suggested criterion is that mania or hypomania develops within 8 weeks of starting an antidepressant for the first time. A chart review of 51 bipolar patients who had extensive life charting found that 82% developed mania while taking an antidepressant—35% of them within 8 weeks.¹⁴ The authors attributed 50% of the risk of a first manic episode and/or cycle acceleration to antidepressants and 50% to spontaneous mood swings. They also noted that:

• an initial manic episode appeared to sensitize patients to subsequent manic episodes and rapid cycling
• mood stabilizers did not seem to prevent these outcomes.

A meta-analysis of 12 randomized, controlled, 4-to 12-week trials among 1,088 patients found antidepressants no more likely than placebo to induce mania in the short term.¹⁵ These trials did not, however, consider less-severe forms of overstimulation and were not designed to determine mania risk in bipolar depressed patients.

Post-mania cycling. Rapid and ultradian cycling and other forms of deterioration are more likely to occur after a manic or hypomanic episode than after a depressive episode.¹⁶

A longitudinal study¹⁷ indicated that antidepressant use did not predictably predate rapid cycling when depression was controlled. The authors, however, looked at the correlation between taking an antidepressant at study entry and rapid cycling over 1 year but did not examine whether antidepressants were started or stopped during the study.¹⁸ Rapid cycling prevalence declined from 19% to 5% during the study, but they did not determine whether withdrawing antidepressants was associated with this change.

In an earlier prospective study, rapid cycling was more severe while patients were taking antidepressants—despite the use of mood stabilizers—and cycling duration decreased when antidepressants were withdrawn.¹⁹

TCAs vs. newer agents. Tricyclic antidepressants (TCAs) are perceived as more likely to induce mania than are selective serotonin reuptake inhibitors (SSRIs) or bupropion. Comparing TCAs’ and newer antidepressants’ switch rates is difficult, however. Most antidepressant trials were designed to show efficacy and safety in unipolar, not bipolar, depression. Moreover, as exclusion criteria have improved with greater awareness of bipolar illness’ polymorphic manifestations, recent studies likely have enrolled fewer bipolar patients—who are most at risk to develop a manic switch—than did earlier TCA trials.

Bupropion, which has been used to treat ADHD, has been thought to have a low risk of inducing mania. In open observation, however, >50% of 11 patients with a history of developing mania with other antidepressants also had a manic switch on bupropion, even though they were taking mood stabilizers.²⁰

Analysis of 155 antidepressant trials in 41 depressed patients found mania risk to be similar with bupropion, SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and other newer antidepressants.²¹ Mania risk doubled when patients were not also taking mood stabilizers.

Going without mood stabilizers. Reports have emerged of patients with bipolar depression taking antidepressants such as fluoxetine and venlafaxine without a mood stabilizer for extended periods, without high rates of mania or mood cycling.^22-24 These reports suggest that some bipolar depressed patients can tolerate antidepressants without a mood stabilizer, although we have no way to identify such patients in advance.

Cycle acceleration and treatment resistance may follow antidepressant-induced mania.²⁵ In DSM-IV field trials, antidepressants appeared to have triggered rapid cycling in some 20% of bipolar patients.²⁶ Mood stabilizers were not particularly effective in patients with treatment-resistant ultradian cycling, but withdrawing antidepressants improved outcome.²⁷

Stimulant-induced mania

Compared with antidepressants, less information is available about stimulant-induced mania and rapid cycling.

Some carefully selected bipolar patients may tolerate ongoing stimulant treatment. For example, in 2 years of open experience with 5 bipolar type I and 3 bipolar type II adults, adding methylphenidate or amphetamine for residual depression or sedation was moderately helpful and did not lead to manic switching or drug misuse.²⁸

On the other hand, affective symptoms worsened in nearly two-thirds of 31 children ages 2 to 5 when treated with stimulants or antidepressants without mood stabilizers. Most of the children also had ADHD, and valproate usually helped.⁶

In 40 patients, mean age 10, who entered the open-label phase of an 8-week trial of divalproex for manic and ADHD symptoms:

• Young Mania Rating Scale (YMRS) scores declined by≥50% in 32 (80%) by week 8, a greater initial response than usually reported in pediatric bipolar disorder with comorbid ADHD.
• ADHD symptoms, measured by Clinical Global Impressions (CGI) scores, did not change significantly.²⁹

Thirty divalproex responders then received mixed amphetamine salts, 10 mg/d, or placebo plus divalproex, crossing over to the other treatment in a 4-week, double-blind trial. ADHD symptoms improved twice as much with the stimulant as with placebo, as measured by CGI scores, whereas YMRS scores did not differ significantly. Among 23 patients who continued the stimulant and divalproex for 12 more weeks, 45% required an increase in stimulant dosage and 1 relapsed into mania.

In this study, ADHD symptoms did not respond to mania treatment but did improve when a stimulant was added. This suggests either that patients had two disorders or that not all bipolar features remit at the same time. The trial’s low stimulant dosage and short duration provide insufficient evidence to support using stimulants over long periods in bipolar children.

LOng-term stimulant effects

Without long-term observations, some investigators have inferred stimulants’ impact on bipolar disorder. A poll of pediatric psychiatrists in the Netherlands, for example, found bipolar disorder in 39 children ages <13 (0.001%) in the previous year, compared with a prevalence of at least 1% in the United States.³ The authors concluded:

• Bipolar disorder emerges at younger ages in the United States than in the Netherlands.
• One reason may be that U.S. psychiatrists have a lower threshold for treating pediatric depression and hyperactivity with antidepressants and stimulants than Dutch psychiatrists do, evoking more-obvious bipolar symptoms at an earlier age.

Observations of 30 U.S. children with a manic episode and ADHD suggested that stimulants can induce manic symptoms:

• Mean age of ADHD onset was 5.5 years.
• Mean age of starting stimulants was 6.9 years.
• Mean age of hypomanic or manic symptom onset was 7.1 years.³⁰

Similarly, in a survey of 34 adolescent manic inpatients, those who had taken stimulants had earlier mania onset (mean age 10.7) than did those who had not taken stimulants (mean age 13.9). Exposure to two stimulants was associated with earlier onset than exposure to one, but comorbid ADHD alone did not affect age of bipolar disorder onset.³¹

The same group¹⁰ reviewed charts of 80 consecutively hospitalized adolescents with a manic or mixed bipolar episode and found stimulant exposure was associated with relatively worse inpatient course, longer length of stay, more emergency medications, and more seclusion and restraint orders. Comorbid ADHD, mixed versus manic episode, and prior antidepressant exposure did not worsen the inpatient course.

A chart review by El-Mallakh et al³² found bipolar disorder was diagnosed at mean age 10.7 in 49 children exposed to antidepressants or stimulants, compared with mean age 12.7 in 44 unexposed children. The exposed group appeared to have tolerated stimulants longer than antidepressants before mania or hypomania emerged.³³

In contrast, a retrospective review by Carlson et al³⁴ of data from a longitudinal study of 75 boys with “hyperkinetic reaction of childhood” found that methylphenidate treatment did not appear more common in boys later diagnosed with bipolar disorder than in those without a bipolar diagnosis. This study had obvious methodologic limitations, lacking a hypothesis and focusing on a population with “minimal brain dysfunction.”

In a reanalysis of data from a 1-month methylphenidate titration trial, Galanter et al³⁵ examined whether some 300 children ages 5 to 12 experienced manic symptoms, using the Diagnostic Interview Schedule for Children or the Child Behavior Checklist. At least during this brief trial, patients with and without manic symptoms showed no differences in response rates or adverse effects with stimulant therapy.

Drug treatment hierarchy

Mood stabilizers. Evidence supports starting all bipolar children with a mood stabilizer such as lithium or valproate (Algorithm). A few patients may tolerate stimulants without mood stabilizers, but the risk is high of inducing mania and precipitating a more complex and treatment-resistant disorder.

Carbamazepine can be effective, but it makes some youths aggressive or disorganized. Antipsychotics have not been tested in controlled trials in bipolar children and are not considered first-line treatments, especially as mood stabilizers. They can be effective for childhood mania, but outpatients needing ADHD treatment usually do not have severe manic syndromes.

Algorithm Reducing mania risk: Using stimulants in children with bipolar disorder

The goal in treating bipolar disorder is to eliminate symptoms as completely as possible. In bipolar children with comorbid ADHD, be certain that subtle hypomanic symptoms—irritability, decreased sleep, hypersensitivity to interactions, psychosis—have remitted, as they could account for continued inattention. Persistent mood lability may indicate incomplete treatment of the mood disorder, which can increase sensitivity to destabilization by a stimulant.

If a child remains inattentive after the mood disorder is controlled, consider whether medications for the mood disorder are to blame. If medications are working well but causing cognitive side effects, a cholinesterase inhibitor may help.

Adding stimulants. If attention problems persist, consider cautiously adding a stimulant. Informed consent includes telling patients and families about the risks of mood destabilization with stimulants, even when used with mood stabilizers.

Increase stimulant dosage very slowly, and monitor the patient closely for emerging mood instability or subtle evidence of dysphoric hypomania. Address hypersensitivity to sounds, increased irritability, or other signs of activation with more-aggressive mood stabilization before assuming that these are ADHD symptoms that require a higher stimulant dosage.

Sustained-release stimulant preparations are probably second-line choices in patients with concomitant bipolar disorder. With long-acting stimulants, any worsening of the mood disorder will take longer to wear off. Antidepressants such as bupropion are potential alternatives to stimulants but are as likely to induce hypomania and mood cycling and may not be as effective.

Compared with stimulants, atomoxetine has a less-potent antidepressant effect and may be somewhat safer, but it is not as effective for ADHD and is longer-acting. Thus, atomoxetine could be a first-line alternative for comorbid ADHD, with stimulants being added if it is not effective. Clonidine can reduce hyperactivity but does not stabilize mood or improve attention.

When an antidepressant has brought bipolar depression into remission, discontinue it slowly to reduce the risk of rebound while continuing mood stabilizers to prevent recurrence. Because ADHD is not cyclical like bipolar depression, inattention returns for many patients when stimulants are withdrawn.

We do not yet know whether the risk of mood destabilization increases with long-term stimulant use, but discontinuation-induced refractoriness has not been reported with stimulants as it has with mood stabilizers and antidepressants. Thus, trying to withdraw stimulants once ADHD symptoms have remitted is prudent, while supplementing the regimen with behavioral treatments. If managing ADHD symptoms requires continued stimulant treatment, monitor the patient closely for mood destabilization.

Related resources

• American Academy of Child and Adolescent Psychiatry. Facts for families: Bipolar disorder in children and teens.
  www.aacap.org/publications/factsFam/bipolar.htm.
• National Institute of Mental Health. Database on ADHD.
  www.nimh.nih.gov/publicat/adhd.cfm.

Drug brand names

• Amphetamine salts • Adderall
• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, others
• Clonidine • Catapres
• Dexmethylphenidate • Focalin
• Fluoxetine • Prozac
• Lithium • Lithobid, others
• Methylphenidate • Concerta,
• Ritalin, others
• Valproate • Depakene, Depakote
• Venlafaxine • Effexor

Disclosures

Dr. Dubovsky receives research support from UCB Pharma, Forest Laboratories, and Solvay Pharmaceuticals, and is a speaker for Janssen Pharmaceutica and Forest Laboratories.

Stimulants are most effective for childhood attention-deficit/hyperactivity disorder (ADHD),¹ but they may induce mania or trigger a treatment-resistant course in children with comorbid bipolar disorder. To help you safely manage these complicated symptoms, this article offers a treatment algorithm and tips to:

• differentiate bipolar and ADHD symptoms
• identify patients at risk for stimulantinduced mania
• choose medications by a hierarchythat may reduce the risk of mood destabilization.

Box 1

Adhd and/or bipolar disorder?

Some 70% to 90% of bipolar children and at least 30% to 40% of bipolar adolescents also have ADHD.² This high comorbidity (Box 1)^3-8 might mean that:

• one disorder predisposes to the other
• one is a precursor of the other
• they share common vulnerabilities or causes
• their symptoms overlap so much that patients with one disorder appear to meet criteria for the other.

Some experts contend that bipolar disorder and ADHD usually can be differentiated. Bipolar children score higher than those with ADHD on measures of anxiety/depression, aggression, and attention problems on the Child Behavior Checklist.⁹ Others believe ADHD symptoms that occur with bipolar disorder are a dimension of bipolar illness rather than a separate disorder.¹⁰

For every DSM-IV-TR diagnostic criterion for ADHD, a corresponding diagnostic criterion or common feature of bipolar disorder can be identified (Table 1). Mania and hypomania are obviously associated with hyperactivity and impulsivity, and tangential thinking and distractibility interfere with attention in many patients with bipolar disorder.

Though most ADHD symptoms can occur in bipolar patients, some features of bipolar illness are not characteristic of ADHD (Table 2). Children with ADHD can become hyper-focused on video games and television, for example, but they usually do not become engrossed in long, complicated books or preoccupied with other people, as can occur in bipolar disorder.

Table 1

How ADHD, bipolar symptoms overlap in three domains

Table 2

Bipolar features not seen in ADHD

A treatment hierarchy

Whether a bipolar patient’s attention problems are features of the primary condition or caused by comorbid ADHD may be unclear, but the treatment implications are important. All antidepressants can induce mania/hypomania and increase the risk of mixed states and mood cycling. Because stimulants have antidepressant properties and because some antidepressants are used to treat ADHD, a systematic approach is necessary when treating inattention in juvenile bipolar disorder.

A treatment hierarchy developed by the American Academy of Child and Adolescent Psychiatry Workgroup on Bipolar Disorder recommends beginning psychosocial approaches, such as training parents in behavior management techniques, and:

• treating bipolar disorder first in children who clearly have both ADHD and bipolar disorder
• adding ADHD treatment if ADHD symptoms persist and impair functioning.²

Who’s at risk for mood destabilization?

No data address differences between bipolar patients whose mood disorders deteriorate with stimulant use and those who remain stable. However, risk factors for mood destabilization that have been reported with antidepressants likely also apply to stimulants (Table 3) because stimulants’ adverse effects in bipolar disorder are probably related to their antidepressant properties.

For example, depressed patients who report that an antidepressant worked within hours to days may have bipolar disorder and be at risk for mood destabilization leading to treatment resistance.¹¹ Antidepressant-induced mania also may be more likely:

• when depression is mixed with hypomanic symptoms such as racing thoughts, excessive talkativeness, aggression, irritability, distractibility, and increased drive¹²
• in patients with a history of antidepressant-induced mania, family history of bipolar disorder, or multiple antidepressant trials.¹³

Similarly, patients who report feeling better immediately after starting a stimulant—especially if they have evidence of elation, increased irritability, more aggression or impulsivity, decreased sleep, or related symptoms—may be developing stimulant-induced hypomania.

Table 3

Risk factors that may increase risk of stimulant-induced mania

Antidepressant-induced mania

Most studies of antidepressant-induced mania have examined outright mania, but hypomania and subsyndromal hypomanic syndromes also may cause significant morbidity and may worsen bipolar disorder’s course. A change in polarity may worsen a patient’s prognosis, but how do we know that antidepressants (or stimulants) caused it?

One suggested criterion is that mania or hypomania develops within 8 weeks of starting an antidepressant for the first time. A chart review of 51 bipolar patients who had extensive life charting found that 82% developed mania while taking an antidepressant—35% of them within 8 weeks.¹⁴ The authors attributed 50% of the risk of a first manic episode and/or cycle acceleration to antidepressants and 50% to spontaneous mood swings. They also noted that:

• an initial manic episode appeared to sensitize patients to subsequent manic episodes and rapid cycling
• mood stabilizers did not seem to prevent these outcomes.

A meta-analysis of 12 randomized, controlled, 4-to 12-week trials among 1,088 patients found antidepressants no more likely than placebo to induce mania in the short term.¹⁵ These trials did not, however, consider less-severe forms of overstimulation and were not designed to determine mania risk in bipolar depressed patients.

Post-mania cycling. Rapid and ultradian cycling and other forms of deterioration are more likely to occur after a manic or hypomanic episode than after a depressive episode.¹⁶

A longitudinal study¹⁷ indicated that antidepressant use did not predictably predate rapid cycling when depression was controlled. The authors, however, looked at the correlation between taking an antidepressant at study entry and rapid cycling over 1 year but did not examine whether antidepressants were started or stopped during the study.¹⁸ Rapid cycling prevalence declined from 19% to 5% during the study, but they did not determine whether withdrawing antidepressants was associated with this change.

In an earlier prospective study, rapid cycling was more severe while patients were taking antidepressants—despite the use of mood stabilizers—and cycling duration decreased when antidepressants were withdrawn.¹⁹

TCAs vs. newer agents. Tricyclic antidepressants (TCAs) are perceived as more likely to induce mania than are selective serotonin reuptake inhibitors (SSRIs) or bupropion. Comparing TCAs’ and newer antidepressants’ switch rates is difficult, however. Most antidepressant trials were designed to show efficacy and safety in unipolar, not bipolar, depression. Moreover, as exclusion criteria have improved with greater awareness of bipolar illness’ polymorphic manifestations, recent studies likely have enrolled fewer bipolar patients—who are most at risk to develop a manic switch—than did earlier TCA trials.

Bupropion, which has been used to treat ADHD, has been thought to have a low risk of inducing mania. In open observation, however, >50% of 11 patients with a history of developing mania with other antidepressants also had a manic switch on bupropion, even though they were taking mood stabilizers.²⁰

Analysis of 155 antidepressant trials in 41 depressed patients found mania risk to be similar with bupropion, SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and other newer antidepressants.²¹ Mania risk doubled when patients were not also taking mood stabilizers.

Going without mood stabilizers. Reports have emerged of patients with bipolar depression taking antidepressants such as fluoxetine and venlafaxine without a mood stabilizer for extended periods, without high rates of mania or mood cycling.^22-24 These reports suggest that some bipolar depressed patients can tolerate antidepressants without a mood stabilizer, although we have no way to identify such patients in advance.

Cycle acceleration and treatment resistance may follow antidepressant-induced mania.²⁵ In DSM-IV field trials, antidepressants appeared to have triggered rapid cycling in some 20% of bipolar patients.²⁶ Mood stabilizers were not particularly effective in patients with treatment-resistant ultradian cycling, but withdrawing antidepressants improved outcome.²⁷

Stimulant-induced mania

Compared with antidepressants, less information is available about stimulant-induced mania and rapid cycling.

Some carefully selected bipolar patients may tolerate ongoing stimulant treatment. For example, in 2 years of open experience with 5 bipolar type I and 3 bipolar type II adults, adding methylphenidate or amphetamine for residual depression or sedation was moderately helpful and did not lead to manic switching or drug misuse.²⁸

On the other hand, affective symptoms worsened in nearly two-thirds of 31 children ages 2 to 5 when treated with stimulants or antidepressants without mood stabilizers. Most of the children also had ADHD, and valproate usually helped.⁶

In 40 patients, mean age 10, who entered the open-label phase of an 8-week trial of divalproex for manic and ADHD symptoms:

• Young Mania Rating Scale (YMRS) scores declined by≥50% in 32 (80%) by week 8, a greater initial response than usually reported in pediatric bipolar disorder with comorbid ADHD.
• ADHD symptoms, measured by Clinical Global Impressions (CGI) scores, did not change significantly.²⁹

Thirty divalproex responders then received mixed amphetamine salts, 10 mg/d, or placebo plus divalproex, crossing over to the other treatment in a 4-week, double-blind trial. ADHD symptoms improved twice as much with the stimulant as with placebo, as measured by CGI scores, whereas YMRS scores did not differ significantly. Among 23 patients who continued the stimulant and divalproex for 12 more weeks, 45% required an increase in stimulant dosage and 1 relapsed into mania.

In this study, ADHD symptoms did not respond to mania treatment but did improve when a stimulant was added. This suggests either that patients had two disorders or that not all bipolar features remit at the same time. The trial’s low stimulant dosage and short duration provide insufficient evidence to support using stimulants over long periods in bipolar children.

LOng-term stimulant effects

Without long-term observations, some investigators have inferred stimulants’ impact on bipolar disorder. A poll of pediatric psychiatrists in the Netherlands, for example, found bipolar disorder in 39 children ages <13 (0.001%) in the previous year, compared with a prevalence of at least 1% in the United States.³ The authors concluded:

• Bipolar disorder emerges at younger ages in the United States than in the Netherlands.
• One reason may be that U.S. psychiatrists have a lower threshold for treating pediatric depression and hyperactivity with antidepressants and stimulants than Dutch psychiatrists do, evoking more-obvious bipolar symptoms at an earlier age.

Observations of 30 U.S. children with a manic episode and ADHD suggested that stimulants can induce manic symptoms:

• Mean age of ADHD onset was 5.5 years.
• Mean age of starting stimulants was 6.9 years.
• Mean age of hypomanic or manic symptom onset was 7.1 years.³⁰

Similarly, in a survey of 34 adolescent manic inpatients, those who had taken stimulants had earlier mania onset (mean age 10.7) than did those who had not taken stimulants (mean age 13.9). Exposure to two stimulants was associated with earlier onset than exposure to one, but comorbid ADHD alone did not affect age of bipolar disorder onset.³¹

The same group¹⁰ reviewed charts of 80 consecutively hospitalized adolescents with a manic or mixed bipolar episode and found stimulant exposure was associated with relatively worse inpatient course, longer length of stay, more emergency medications, and more seclusion and restraint orders. Comorbid ADHD, mixed versus manic episode, and prior antidepressant exposure did not worsen the inpatient course.

A chart review by El-Mallakh et al³² found bipolar disorder was diagnosed at mean age 10.7 in 49 children exposed to antidepressants or stimulants, compared with mean age 12.7 in 44 unexposed children. The exposed group appeared to have tolerated stimulants longer than antidepressants before mania or hypomania emerged.³³

In contrast, a retrospective review by Carlson et al³⁴ of data from a longitudinal study of 75 boys with “hyperkinetic reaction of childhood” found that methylphenidate treatment did not appear more common in boys later diagnosed with bipolar disorder than in those without a bipolar diagnosis. This study had obvious methodologic limitations, lacking a hypothesis and focusing on a population with “minimal brain dysfunction.”

In a reanalysis of data from a 1-month methylphenidate titration trial, Galanter et al³⁵ examined whether some 300 children ages 5 to 12 experienced manic symptoms, using the Diagnostic Interview Schedule for Children or the Child Behavior Checklist. At least during this brief trial, patients with and without manic symptoms showed no differences in response rates or adverse effects with stimulant therapy.

Drug treatment hierarchy

Mood stabilizers. Evidence supports starting all bipolar children with a mood stabilizer such as lithium or valproate (Algorithm). A few patients may tolerate stimulants without mood stabilizers, but the risk is high of inducing mania and precipitating a more complex and treatment-resistant disorder.

Carbamazepine can be effective, but it makes some youths aggressive or disorganized. Antipsychotics have not been tested in controlled trials in bipolar children and are not considered first-line treatments, especially as mood stabilizers. They can be effective for childhood mania, but outpatients needing ADHD treatment usually do not have severe manic syndromes.

Algorithm Reducing mania risk: Using stimulants in children with bipolar disorder

The goal in treating bipolar disorder is to eliminate symptoms as completely as possible. In bipolar children with comorbid ADHD, be certain that subtle hypomanic symptoms—irritability, decreased sleep, hypersensitivity to interactions, psychosis—have remitted, as they could account for continued inattention. Persistent mood lability may indicate incomplete treatment of the mood disorder, which can increase sensitivity to destabilization by a stimulant.

If a child remains inattentive after the mood disorder is controlled, consider whether medications for the mood disorder are to blame. If medications are working well but causing cognitive side effects, a cholinesterase inhibitor may help.

Adding stimulants. If attention problems persist, consider cautiously adding a stimulant. Informed consent includes telling patients and families about the risks of mood destabilization with stimulants, even when used with mood stabilizers.

Increase stimulant dosage very slowly, and monitor the patient closely for emerging mood instability or subtle evidence of dysphoric hypomania. Address hypersensitivity to sounds, increased irritability, or other signs of activation with more-aggressive mood stabilization before assuming that these are ADHD symptoms that require a higher stimulant dosage.

Sustained-release stimulant preparations are probably second-line choices in patients with concomitant bipolar disorder. With long-acting stimulants, any worsening of the mood disorder will take longer to wear off. Antidepressants such as bupropion are potential alternatives to stimulants but are as likely to induce hypomania and mood cycling and may not be as effective.

Compared with stimulants, atomoxetine has a less-potent antidepressant effect and may be somewhat safer, but it is not as effective for ADHD and is longer-acting. Thus, atomoxetine could be a first-line alternative for comorbid ADHD, with stimulants being added if it is not effective. Clonidine can reduce hyperactivity but does not stabilize mood or improve attention.

When an antidepressant has brought bipolar depression into remission, discontinue it slowly to reduce the risk of rebound while continuing mood stabilizers to prevent recurrence. Because ADHD is not cyclical like bipolar depression, inattention returns for many patients when stimulants are withdrawn.

We do not yet know whether the risk of mood destabilization increases with long-term stimulant use, but discontinuation-induced refractoriness has not been reported with stimulants as it has with mood stabilizers and antidepressants. Thus, trying to withdraw stimulants once ADHD symptoms have remitted is prudent, while supplementing the regimen with behavioral treatments. If managing ADHD symptoms requires continued stimulant treatment, monitor the patient closely for mood destabilization.

Related resources

• American Academy of Child and Adolescent Psychiatry. Facts for families: Bipolar disorder in children and teens.
  www.aacap.org/publications/factsFam/bipolar.htm.
• National Institute of Mental Health. Database on ADHD.
  www.nimh.nih.gov/publicat/adhd.cfm.

Drug brand names

• Amphetamine salts • Adderall
• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, others
• Clonidine • Catapres
• Dexmethylphenidate • Focalin
• Fluoxetine • Prozac
• Lithium • Lithobid, others
• Methylphenidate • Concerta,
• Ritalin, others
• Valproate • Depakene, Depakote
• Venlafaxine • Effexor

Disclosures

Dr. Dubovsky receives research support from UCB Pharma, Forest Laboratories, and Solvay Pharmaceuticals, and is a speaker for Janssen Pharmaceutica and Forest Laboratories.

Stimulants are most effective for childhood attention-deficit/hyperactivity disorder (ADHD),¹ but they may induce mania or trigger a treatment-resistant course in children with comorbid bipolar disorder. To help you safely manage these complicated symptoms, this article offers a treatment algorithm and tips to:

• differentiate bipolar and ADHD symptoms
• identify patients at risk for stimulantinduced mania
• choose medications by a hierarchythat may reduce the risk of mood destabilization.

Box 1

Adhd and/or bipolar disorder?

Some 70% to 90% of bipolar children and at least 30% to 40% of bipolar adolescents also have ADHD.² This high comorbidity (Box 1)^3-8 might mean that:

• one disorder predisposes to the other
• one is a precursor of the other
• they share common vulnerabilities or causes
• their symptoms overlap so much that patients with one disorder appear to meet criteria for the other.

Some experts contend that bipolar disorder and ADHD usually can be differentiated. Bipolar children score higher than those with ADHD on measures of anxiety/depression, aggression, and attention problems on the Child Behavior Checklist.⁹ Others believe ADHD symptoms that occur with bipolar disorder are a dimension of bipolar illness rather than a separate disorder.¹⁰

For every DSM-IV-TR diagnostic criterion for ADHD, a corresponding diagnostic criterion or common feature of bipolar disorder can be identified (Table 1). Mania and hypomania are obviously associated with hyperactivity and impulsivity, and tangential thinking and distractibility interfere with attention in many patients with bipolar disorder.

Though most ADHD symptoms can occur in bipolar patients, some features of bipolar illness are not characteristic of ADHD (Table 2). Children with ADHD can become hyper-focused on video games and television, for example, but they usually do not become engrossed in long, complicated books or preoccupied with other people, as can occur in bipolar disorder.

Table 1

How ADHD, bipolar symptoms overlap in three domains

Table 2

Bipolar features not seen in ADHD

A treatment hierarchy

Whether a bipolar patient’s attention problems are features of the primary condition or caused by comorbid ADHD may be unclear, but the treatment implications are important. All antidepressants can induce mania/hypomania and increase the risk of mixed states and mood cycling. Because stimulants have antidepressant properties and because some antidepressants are used to treat ADHD, a systematic approach is necessary when treating inattention in juvenile bipolar disorder.

A treatment hierarchy developed by the American Academy of Child and Adolescent Psychiatry Workgroup on Bipolar Disorder recommends beginning psychosocial approaches, such as training parents in behavior management techniques, and:

• treating bipolar disorder first in children who clearly have both ADHD and bipolar disorder
• adding ADHD treatment if ADHD symptoms persist and impair functioning.²

Who’s at risk for mood destabilization?

No data address differences between bipolar patients whose mood disorders deteriorate with stimulant use and those who remain stable. However, risk factors for mood destabilization that have been reported with antidepressants likely also apply to stimulants (Table 3) because stimulants’ adverse effects in bipolar disorder are probably related to their antidepressant properties.

For example, depressed patients who report that an antidepressant worked within hours to days may have bipolar disorder and be at risk for mood destabilization leading to treatment resistance.¹¹ Antidepressant-induced mania also may be more likely:

• when depression is mixed with hypomanic symptoms such as racing thoughts, excessive talkativeness, aggression, irritability, distractibility, and increased drive¹²
• in patients with a history of antidepressant-induced mania, family history of bipolar disorder, or multiple antidepressant trials.¹³

Similarly, patients who report feeling better immediately after starting a stimulant—especially if they have evidence of elation, increased irritability, more aggression or impulsivity, decreased sleep, or related symptoms—may be developing stimulant-induced hypomania.

Table 3

Risk factors that may increase risk of stimulant-induced mania

Antidepressant-induced mania

Most studies of antidepressant-induced mania have examined outright mania, but hypomania and subsyndromal hypomanic syndromes also may cause significant morbidity and may worsen bipolar disorder’s course. A change in polarity may worsen a patient’s prognosis, but how do we know that antidepressants (or stimulants) caused it?

One suggested criterion is that mania or hypomania develops within 8 weeks of starting an antidepressant for the first time. A chart review of 51 bipolar patients who had extensive life charting found that 82% developed mania while taking an antidepressant—35% of them within 8 weeks.¹⁴ The authors attributed 50% of the risk of a first manic episode and/or cycle acceleration to antidepressants and 50% to spontaneous mood swings. They also noted that:

• an initial manic episode appeared to sensitize patients to subsequent manic episodes and rapid cycling
• mood stabilizers did not seem to prevent these outcomes.

A meta-analysis of 12 randomized, controlled, 4-to 12-week trials among 1,088 patients found antidepressants no more likely than placebo to induce mania in the short term.¹⁵ These trials did not, however, consider less-severe forms of overstimulation and were not designed to determine mania risk in bipolar depressed patients.

Post-mania cycling. Rapid and ultradian cycling and other forms of deterioration are more likely to occur after a manic or hypomanic episode than after a depressive episode.¹⁶

A longitudinal study¹⁷ indicated that antidepressant use did not predictably predate rapid cycling when depression was controlled. The authors, however, looked at the correlation between taking an antidepressant at study entry and rapid cycling over 1 year but did not examine whether antidepressants were started or stopped during the study.¹⁸ Rapid cycling prevalence declined from 19% to 5% during the study, but they did not determine whether withdrawing antidepressants was associated with this change.

In an earlier prospective study, rapid cycling was more severe while patients were taking antidepressants—despite the use of mood stabilizers—and cycling duration decreased when antidepressants were withdrawn.¹⁹

TCAs vs. newer agents. Tricyclic antidepressants (TCAs) are perceived as more likely to induce mania than are selective serotonin reuptake inhibitors (SSRIs) or bupropion. Comparing TCAs’ and newer antidepressants’ switch rates is difficult, however. Most antidepressant trials were designed to show efficacy and safety in unipolar, not bipolar, depression. Moreover, as exclusion criteria have improved with greater awareness of bipolar illness’ polymorphic manifestations, recent studies likely have enrolled fewer bipolar patients—who are most at risk to develop a manic switch—than did earlier TCA trials.

Bupropion, which has been used to treat ADHD, has been thought to have a low risk of inducing mania. In open observation, however, >50% of 11 patients with a history of developing mania with other antidepressants also had a manic switch on bupropion, even though they were taking mood stabilizers.²⁰

Analysis of 155 antidepressant trials in 41 depressed patients found mania risk to be similar with bupropion, SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and other newer antidepressants.²¹ Mania risk doubled when patients were not also taking mood stabilizers.

Going without mood stabilizers. Reports have emerged of patients with bipolar depression taking antidepressants such as fluoxetine and venlafaxine without a mood stabilizer for extended periods, without high rates of mania or mood cycling.^22-24 These reports suggest that some bipolar depressed patients can tolerate antidepressants without a mood stabilizer, although we have no way to identify such patients in advance.

Cycle acceleration and treatment resistance may follow antidepressant-induced mania.²⁵ In DSM-IV field trials, antidepressants appeared to have triggered rapid cycling in some 20% of bipolar patients.²⁶ Mood stabilizers were not particularly effective in patients with treatment-resistant ultradian cycling, but withdrawing antidepressants improved outcome.²⁷

Stimulant-induced mania

Compared with antidepressants, less information is available about stimulant-induced mania and rapid cycling.

Some carefully selected bipolar patients may tolerate ongoing stimulant treatment. For example, in 2 years of open experience with 5 bipolar type I and 3 bipolar type II adults, adding methylphenidate or amphetamine for residual depression or sedation was moderately helpful and did not lead to manic switching or drug misuse.²⁸

On the other hand, affective symptoms worsened in nearly two-thirds of 31 children ages 2 to 5 when treated with stimulants or antidepressants without mood stabilizers. Most of the children also had ADHD, and valproate usually helped.⁶

In 40 patients, mean age 10, who entered the open-label phase of an 8-week trial of divalproex for manic and ADHD symptoms:

• Young Mania Rating Scale (YMRS) scores declined by≥50% in 32 (80%) by week 8, a greater initial response than usually reported in pediatric bipolar disorder with comorbid ADHD.
• ADHD symptoms, measured by Clinical Global Impressions (CGI) scores, did not change significantly.²⁹

Thirty divalproex responders then received mixed amphetamine salts, 10 mg/d, or placebo plus divalproex, crossing over to the other treatment in a 4-week, double-blind trial. ADHD symptoms improved twice as much with the stimulant as with placebo, as measured by CGI scores, whereas YMRS scores did not differ significantly. Among 23 patients who continued the stimulant and divalproex for 12 more weeks, 45% required an increase in stimulant dosage and 1 relapsed into mania.

In this study, ADHD symptoms did not respond to mania treatment but did improve when a stimulant was added. This suggests either that patients had two disorders or that not all bipolar features remit at the same time. The trial’s low stimulant dosage and short duration provide insufficient evidence to support using stimulants over long periods in bipolar children.

LOng-term stimulant effects

Without long-term observations, some investigators have inferred stimulants’ impact on bipolar disorder. A poll of pediatric psychiatrists in the Netherlands, for example, found bipolar disorder in 39 children ages <13 (0.001%) in the previous year, compared with a prevalence of at least 1% in the United States.³ The authors concluded:

• Bipolar disorder emerges at younger ages in the United States than in the Netherlands.
• One reason may be that U.S. psychiatrists have a lower threshold for treating pediatric depression and hyperactivity with antidepressants and stimulants than Dutch psychiatrists do, evoking more-obvious bipolar symptoms at an earlier age.

Observations of 30 U.S. children with a manic episode and ADHD suggested that stimulants can induce manic symptoms:

• Mean age of ADHD onset was 5.5 years.
• Mean age of starting stimulants was 6.9 years.
• Mean age of hypomanic or manic symptom onset was 7.1 years.³⁰

Similarly, in a survey of 34 adolescent manic inpatients, those who had taken stimulants had earlier mania onset (mean age 10.7) than did those who had not taken stimulants (mean age 13.9). Exposure to two stimulants was associated with earlier onset than exposure to one, but comorbid ADHD alone did not affect age of bipolar disorder onset.³¹

The same group¹⁰ reviewed charts of 80 consecutively hospitalized adolescents with a manic or mixed bipolar episode and found stimulant exposure was associated with relatively worse inpatient course, longer length of stay, more emergency medications, and more seclusion and restraint orders. Comorbid ADHD, mixed versus manic episode, and prior antidepressant exposure did not worsen the inpatient course.

A chart review by El-Mallakh et al³² found bipolar disorder was diagnosed at mean age 10.7 in 49 children exposed to antidepressants or stimulants, compared with mean age 12.7 in 44 unexposed children. The exposed group appeared to have tolerated stimulants longer than antidepressants before mania or hypomania emerged.³³

In contrast, a retrospective review by Carlson et al³⁴ of data from a longitudinal study of 75 boys with “hyperkinetic reaction of childhood” found that methylphenidate treatment did not appear more common in boys later diagnosed with bipolar disorder than in those without a bipolar diagnosis. This study had obvious methodologic limitations, lacking a hypothesis and focusing on a population with “minimal brain dysfunction.”

In a reanalysis of data from a 1-month methylphenidate titration trial, Galanter et al³⁵ examined whether some 300 children ages 5 to 12 experienced manic symptoms, using the Diagnostic Interview Schedule for Children or the Child Behavior Checklist. At least during this brief trial, patients with and without manic symptoms showed no differences in response rates or adverse effects with stimulant therapy.

Drug treatment hierarchy

Mood stabilizers. Evidence supports starting all bipolar children with a mood stabilizer such as lithium or valproate (Algorithm). A few patients may tolerate stimulants without mood stabilizers, but the risk is high of inducing mania and precipitating a more complex and treatment-resistant disorder.

Carbamazepine can be effective, but it makes some youths aggressive or disorganized. Antipsychotics have not been tested in controlled trials in bipolar children and are not considered first-line treatments, especially as mood stabilizers. They can be effective for childhood mania, but outpatients needing ADHD treatment usually do not have severe manic syndromes.

Algorithm Reducing mania risk: Using stimulants in children with bipolar disorder

The goal in treating bipolar disorder is to eliminate symptoms as completely as possible. In bipolar children with comorbid ADHD, be certain that subtle hypomanic symptoms—irritability, decreased sleep, hypersensitivity to interactions, psychosis—have remitted, as they could account for continued inattention. Persistent mood lability may indicate incomplete treatment of the mood disorder, which can increase sensitivity to destabilization by a stimulant.

If a child remains inattentive after the mood disorder is controlled, consider whether medications for the mood disorder are to blame. If medications are working well but causing cognitive side effects, a cholinesterase inhibitor may help.

Adding stimulants. If attention problems persist, consider cautiously adding a stimulant. Informed consent includes telling patients and families about the risks of mood destabilization with stimulants, even when used with mood stabilizers.

Increase stimulant dosage very slowly, and monitor the patient closely for emerging mood instability or subtle evidence of dysphoric hypomania. Address hypersensitivity to sounds, increased irritability, or other signs of activation with more-aggressive mood stabilization before assuming that these are ADHD symptoms that require a higher stimulant dosage.

Sustained-release stimulant preparations are probably second-line choices in patients with concomitant bipolar disorder. With long-acting stimulants, any worsening of the mood disorder will take longer to wear off. Antidepressants such as bupropion are potential alternatives to stimulants but are as likely to induce hypomania and mood cycling and may not be as effective.

Compared with stimulants, atomoxetine has a less-potent antidepressant effect and may be somewhat safer, but it is not as effective for ADHD and is longer-acting. Thus, atomoxetine could be a first-line alternative for comorbid ADHD, with stimulants being added if it is not effective. Clonidine can reduce hyperactivity but does not stabilize mood or improve attention.

When an antidepressant has brought bipolar depression into remission, discontinue it slowly to reduce the risk of rebound while continuing mood stabilizers to prevent recurrence. Because ADHD is not cyclical like bipolar depression, inattention returns for many patients when stimulants are withdrawn.

We do not yet know whether the risk of mood destabilization increases with long-term stimulant use, but discontinuation-induced refractoriness has not been reported with stimulants as it has with mood stabilizers and antidepressants. Thus, trying to withdraw stimulants once ADHD symptoms have remitted is prudent, while supplementing the regimen with behavioral treatments. If managing ADHD symptoms requires continued stimulant treatment, monitor the patient closely for mood destabilization.

Related resources

• American Academy of Child and Adolescent Psychiatry. Facts for families: Bipolar disorder in children and teens.
  www.aacap.org/publications/factsFam/bipolar.htm.
• National Institute of Mental Health. Database on ADHD.
  www.nimh.nih.gov/publicat/adhd.cfm.

Drug brand names

• Amphetamine salts • Adderall
• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, others
• Clonidine • Catapres
• Dexmethylphenidate • Focalin
• Fluoxetine • Prozac
• Lithium • Lithobid, others
• Methylphenidate • Concerta,
• Ritalin, others
• Valproate • Depakene, Depakote
• Venlafaxine • Effexor

Disclosures

Dr. Dubovsky receives research support from UCB Pharma, Forest Laboratories, and Solvay Pharmaceuticals, and is a speaker for Janssen Pharmaceutica and Forest Laboratories.

Sadly, parental neglect and child abuse are very common in the United States and worldwide. Patients abused or exploited in childhood, who experience neglect or the loss of a parent during childhood, are haunted by these experiences.

Considerable evidence from laboratory animal and clinical studies indicate that stressful or traumatic events early in development have long-lasting effects on brain development. In particular, the neural and endocrine systems mediating the response to stress exhibit persistent alterations after adverse childhood events.

Clinically, patients with a history of childhood trauma often struggle with variable symptom complexes including both depression and anxiety. In this article, we review evidence that depression in patients with a history of early life stress (ELS) is biologically and clinically distinct from depression in patients without childhood abuse or neglect.

Data linking ELS to depression

Conservative estimates suggest that every year in the United States more than 1 million children are exposed to sexual or physical abuse or severe neglect.¹ Unfortunately, this is only the tip of the iceberg. Emotional abuse is by definition comorbid with sexual and physical abuse and may occur alone at even higher rates.

Psychiatric sequelae of child abuse have been studied in adult survivors in considerable detail (Table). Women abused as children report greater numbers of depression, anxiety, somatic, and substance abuse symptoms compared with women without such a history.² Not only are these women at increased risk for attempted suicide, but they attempt suicide at a rate that is proportional to the number of early life traumatic events that occurred during childhood.³ Men also are at increased risk for depression in the wake of child abuse.⁴

Sexual abuse in particular is a marker of especially severe childhood trauma. Depressed women who were sexually abused as children report more childhood physical abuse, childhood emotional abuse, parental conflict, and an earlier onset of depression than depressed women without a history of sexual abuse.⁵

Finally, recent data drawn from the National Comorbidity Survey suggest that child abuse and neglect may independently elevate risk for several stress-related diseases including cardiac disease, peptic ulcer, autoimmune disease, diabetes mellitus, and lung disease.⁶

Table

Early life stress as a risk factor for mood and anxiety disorders

Depression and the biology of stress

Preclinical research using laboratory animals and clinical research with humans has provided significant insight into the relationship between the pathophysiology of depression and the neurobiology of stress. A burgeoning database suggests that disruption of the neural systems mediating the stress response plays a significant role in the etiology of certain forms of depression and anxiety.⁷ Much of this work has focused on the preeminent role of corticotropin-releasing factor (CRF) in this process (Figure).

CRF is one of the principal mediators of the mammalian stress response. One CRF system is composed of neurons of the paraventricular nuclei of the hypothalamus that project nerve terminals to the median eminence, where they secrete CRF into the hypophyseal portal system. CRF is then transported within the portal system to the anterior pituitary where it acts on corticotrophs to increase adrenocorticotrophic hormone (ACTH) secretion, thereby controlling hypothalamic-pituitary-adrenal (HPA) axis activity.⁸ CRF is also found in extrahypothalamic brain areas where it functions, in concert with the hypothalamic CRF system, as a neurotransmitter in coordinating the behavioral, autonomic, and immune responses to stress.⁹

Direct central nervous system (CNS) administration of CRF in laboratory animals, typically rodents or nonhuman primates, results in activation of the autonomic nervous system leading to elevation of peripheral catecholamines, modification of gastrointestinal activity, increased heart rate and increased blood pressure. In addition, changes in behavior similar to those observed in human depression occur, including disturbed sleep patterns, reduced food intake, decreased reproductive behavior, and enhanced fear conditioning.^10,11

In humans, elevated CRF concentrations are found in the cerebrospinal fluid (CSF) of patients with depression^12,13 and of combat veterans with posttraumatic stress disorder (PTSD).^14,15 Further, postmortem studies of suicide victims have revealed decreased density of CRF receptors in the frontal cortex,¹⁶ decreased expression of CRF receptor mRNA and increased CRF concentrations in the frontal cortex when compared with controls,¹⁷ and increased concentrations of cisternal CSF CRF.¹⁸ Collectively, these clinical data are consistent with the hypothesis that CRF is chronically hypersecreted in patients with depression or PTSD.

Figure Biological and behavioral effects of chronic CRF hypersecretion

A distinct ‘ELS depression’?

Depression has a complex etiology based on interacting contributions from genes and the environment¹⁹ that may ultimately result in biologically and clinically distinct forms of depression.²⁰ Exposure to stress, particularly during neurobiologically vulnerable periods of development, may be one means whereby the environment influences the development of depression in genetically susceptible individuals.²¹

Heredity. Kendler and colleagues²² studied 1,404 female adult twins and observed that childhood sexual abuse was associated with both an increased risk for major depression and a marked increased sensitivity to the depressogenic effects of stressful life events. Moreover, research in human gene-environment interactions has identified a functional polymorphism in the promoter region of the gene for the serotonin transporter which appears to moderate the influence of stressful life events on the development of depression and potential for suicide.^23,24

Environment. Similarly, a key variable in determining the clinical outcome of childhood trauma may be the developmental timing of the abuse. Women abused before age 13 are at equivalent risk for developing PTSD or major depressive disorder (MDD), whereas women abused after age 13 are more likely to develop PTSD.²⁵

Thus a major challenge in depression research is to understand the biological mechanisms that mediate the effects of trauma during development through the genetic windows of vulnerability and resilience.

Animal models of ELS have been studied to elucidate the neurobiological consequences of early life trauma in adult humans. This work has largely been performed in rodents and nonhuman primates using a variety of experimental paradigms.

Although a comprehensive review of these data is beyond the scope of this article, ELS in laboratory animals has consistently been found to produce both short- and long-term adverse neurobiological and endocrine effects as well as cognitive dysfunction and abnormal behavior.²¹ One possible mechanism mediating these effects is a persistent hyperresponsiveness of different components of the HPA axis following exposure to stress.

Studies in adult women have sought to uncover the long-term effects of ELS (prepubertal physical or sexual abuse) on reactivity of the HPA axis in response to the Trier Social Stress Test, a standardized psychosocial stress test.²⁶ It consists of the subject giving a 10-minute speech and performing a mental arithmetic task in front of a panel of stern-appearing evaluators. Variables measured include heart rate, plasma ACTH, and cortisol concentration at intervals before and after the performance component of the test. The four groups in this study included:

• women without psychiatric illness or history of ELS serving as a control group (CON)
• depressed women without a history of ELS (non-ELS/MDD)
• depressed women with a history of ELS (ELS/MDD)
• non-depressed women with a history of ELS (ELS/non-MDD).

The largest ACTH and cortisol responses and increases in heart rate following this stress exposure were seen in the ELS/MDD group. In fact, the ACTH response of these women was more than 6 times greater than that observed in the control group. The ELS/MDD group of women also had greater rates of comorbid PTSD (85%) in comparison to the other experimental groups as well.

These data are consistent with the hypothesis that ELS produces enduring sensitization of the HPA axis and autonomic nervous system response to stress. This phenomenon may constitute an important etiological element in the development of stress-related adult psychiatric illnesses such as depression or PTSD.

To further explore the hypothesis that ELS alters set points of the HPA axis, we sought to characterize the effects of standard HPA axis challenge tests (CRF stimulation test and ACTH1-24 stimulation test) in a similar population of women.²⁷ Depressed women with a history of ELS and depressed women without a history of ELS both exhibited a blunted ACTH response to infusion of exogenous CRF. Conversely, women with a history of ELS but without current depression had an increased ACTH response following CRF infusion.

With respect to the ACTH1-24 stimulation test, abused women who were not depressed had lower plasma cortisol levels at baseline and after administration of ACTH1-24. Similar to the findings of our previous study,²⁶ women with MDD and a history of ELS were more likely to report current life stress and to also have comorbid PTSD than women with ELS who were not depressed. Blunting of the ACTH response to exogenous CRF in depressed women with a history of ELS may in part be secondary to acute downregulation of pituitary CRF receptors as a result of chronic CRF hypersecretion.

More recently, Carpenter and colleagues²⁸ evaluated the relationship between the perception of ELS and CSF CRF in patients with depression and healthy control subjects. The perception of ELS predicted CSF CRF concentration independent of the presence or absence of depression. Further, and most interestingly, the developmental timing of the stress exposure was predictive of either relatively increased or decreased CSF CRF. ELS before age 6 was associated with elevated CSF CRF, whereas perinatal and preteen exposure to stressful events was associated with decreased CSF CRF.

Brain structure changes? In addition to the neuroendocrine changes observed in patients with ELS, there is evidence that ELS may also alter brain structure. Reduced hippocampal volume is found in some but not all patients with unipolar depression.²⁹ In patients with a history of depression who also have hippocampal atrophy, the extent of atrophy is greater in patients with higher total lifetime duration of depression.^30,31

Patients with ELS also have been found to have decreased hippocampal volume.^32,33 However, previous structural imaging studies have not controlled for the presence of ELS when attempting to determine the relationship between depression and structural changes in the hippocampus, and this methodologic confound may explain in part the inconsistent relationship between altered hippocampal volume and depression.

To evaluate this hypothesis, hippocampal volume was measured in depressed women with and without a history of ELS and in a control group of women. Reduced hippocampal volume was found to occur solely in depressed women with a history of ELS. Depressed women without ELS and women from the control group had similar hippocampal volumes.³⁴ These data suggest that previous reports of reduced hippocampal size in patients with depression may in fact be related to a history of ELS rather than depression.

Treatment implications

The data discussed in this paper indicate that patients with depression and a history of ELS may constitute a unique subgroup among depressed patients as a whole. A growing body of evidence suggests that depressed patients with ELS may also be unique with respect to their response to treatment.

ELS has been found to impact the clinical response of patients to pharmacotherapy with either dysthymia or depression.^35,36 Further, patients with depression and a history of ELS have been reported to exhibit increased rates of relapse following treatment of depression.³⁷ The course of depression in individuals with ELS is often characterized by chronicity.

ELS and therapeutic response, Recently, our group has sought to determine whether ELS in patients with chronic depression moderates their response to pharmacotherapy or psychotherapy.³⁸ In this study, data from a large multicenter trial³⁹ originally designed to compare the relative efficacy of pharmacotherapy (nefazodone), psychotherapy (Cognitive Behavioral Analysis System of Psychotherapy), or their combination in the treatment of chronic depression was reanalyzed by stratifying patients based on the presence or absence of ELS. In the overall sample of patients with chronic depression, psychotherapy and pharmacotherapy were comparable in efficacy but significantly less effective than their combination.

ELS in chronically depressed patients was highly prevalent. Approximately one-third experienced loss of a parent before age 15, 45% experienced childhood physical abuse, 16% experienced childhood sexual abuse, and 10% experienced neglect. Most significantly, depressed patients with a history of ELS had a superior response to psychotherapy alone compared with antidepressant monotherapy. In addition, combination therapy was only slightly more effective than psychotherapy alone in the group of depressed patients with ELS.

These data suggest that ELS is common in the population of patients with chronic depression and that psychotherapy is a critical element in the treatment of depressed patients with ELS⁴⁰ (Box). However, it will be important in future studies to ascertain whether the differences in treatment response for psychotherapy compared with antidepressant in patients with ELS and depression are able to be replicated with the SSRI class of antidepressants.

BOX

Related resources

• Depression and Bipolar Support Alliance. www.dbsalliance.org.
• National Clearinghouse on Child Abuse and Neglect. http://nccanch.acf.hhs.gov.
• Charney DS, Nemeroff CB. The peace of mind prescription: An authoritative guide to finding the most effective treatment for anxiety and depression. Boston: Houghton Mifflin, 2004.

Drug brand name

• Nefazodone • Serzone

Disclosure

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

Dr. Nemeroff receives research grants from or is a consultant/speaker for Abbott Laboratories, Acadia Pharmaceuticals, American Foundation for Suicide Prevention, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Corcept Therapeutics, Cyberonics, Cypress Biosciences, Eli Lilly and Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co., Neurocrine Biosciences, Otsuka Inc., Pfizer Inc., Sanofi Aventis, and Wyeth.

Acknowledgement

Supported by NIH MH-42088, MH-52899 (CBN), and NIH NCRRM01-RR00039 to Emory University.

Sadly, parental neglect and child abuse are very common in the United States and worldwide. Patients abused or exploited in childhood, who experience neglect or the loss of a parent during childhood, are haunted by these experiences.

Considerable evidence from laboratory animal and clinical studies indicate that stressful or traumatic events early in development have long-lasting effects on brain development. In particular, the neural and endocrine systems mediating the response to stress exhibit persistent alterations after adverse childhood events.

Clinically, patients with a history of childhood trauma often struggle with variable symptom complexes including both depression and anxiety. In this article, we review evidence that depression in patients with a history of early life stress (ELS) is biologically and clinically distinct from depression in patients without childhood abuse or neglect.

Data linking ELS to depression

Conservative estimates suggest that every year in the United States more than 1 million children are exposed to sexual or physical abuse or severe neglect.¹ Unfortunately, this is only the tip of the iceberg. Emotional abuse is by definition comorbid with sexual and physical abuse and may occur alone at even higher rates.

Psychiatric sequelae of child abuse have been studied in adult survivors in considerable detail (Table). Women abused as children report greater numbers of depression, anxiety, somatic, and substance abuse symptoms compared with women without such a history.² Not only are these women at increased risk for attempted suicide, but they attempt suicide at a rate that is proportional to the number of early life traumatic events that occurred during childhood.³ Men also are at increased risk for depression in the wake of child abuse.⁴

Sexual abuse in particular is a marker of especially severe childhood trauma. Depressed women who were sexually abused as children report more childhood physical abuse, childhood emotional abuse, parental conflict, and an earlier onset of depression than depressed women without a history of sexual abuse.⁵

Finally, recent data drawn from the National Comorbidity Survey suggest that child abuse and neglect may independently elevate risk for several stress-related diseases including cardiac disease, peptic ulcer, autoimmune disease, diabetes mellitus, and lung disease.⁶

Table

Early life stress as a risk factor for mood and anxiety disorders

Depression and the biology of stress

Preclinical research using laboratory animals and clinical research with humans has provided significant insight into the relationship between the pathophysiology of depression and the neurobiology of stress. A burgeoning database suggests that disruption of the neural systems mediating the stress response plays a significant role in the etiology of certain forms of depression and anxiety.⁷ Much of this work has focused on the preeminent role of corticotropin-releasing factor (CRF) in this process (Figure).

CRF is one of the principal mediators of the mammalian stress response. One CRF system is composed of neurons of the paraventricular nuclei of the hypothalamus that project nerve terminals to the median eminence, where they secrete CRF into the hypophyseal portal system. CRF is then transported within the portal system to the anterior pituitary where it acts on corticotrophs to increase adrenocorticotrophic hormone (ACTH) secretion, thereby controlling hypothalamic-pituitary-adrenal (HPA) axis activity.⁸ CRF is also found in extrahypothalamic brain areas where it functions, in concert with the hypothalamic CRF system, as a neurotransmitter in coordinating the behavioral, autonomic, and immune responses to stress.⁹

Direct central nervous system (CNS) administration of CRF in laboratory animals, typically rodents or nonhuman primates, results in activation of the autonomic nervous system leading to elevation of peripheral catecholamines, modification of gastrointestinal activity, increased heart rate and increased blood pressure. In addition, changes in behavior similar to those observed in human depression occur, including disturbed sleep patterns, reduced food intake, decreased reproductive behavior, and enhanced fear conditioning.^10,11

In humans, elevated CRF concentrations are found in the cerebrospinal fluid (CSF) of patients with depression^12,13 and of combat veterans with posttraumatic stress disorder (PTSD).^14,15 Further, postmortem studies of suicide victims have revealed decreased density of CRF receptors in the frontal cortex,¹⁶ decreased expression of CRF receptor mRNA and increased CRF concentrations in the frontal cortex when compared with controls,¹⁷ and increased concentrations of cisternal CSF CRF.¹⁸ Collectively, these clinical data are consistent with the hypothesis that CRF is chronically hypersecreted in patients with depression or PTSD.

Figure Biological and behavioral effects of chronic CRF hypersecretion

A distinct ‘ELS depression’?

Depression has a complex etiology based on interacting contributions from genes and the environment¹⁹ that may ultimately result in biologically and clinically distinct forms of depression.²⁰ Exposure to stress, particularly during neurobiologically vulnerable periods of development, may be one means whereby the environment influences the development of depression in genetically susceptible individuals.²¹

Heredity. Kendler and colleagues²² studied 1,404 female adult twins and observed that childhood sexual abuse was associated with both an increased risk for major depression and a marked increased sensitivity to the depressogenic effects of stressful life events. Moreover, research in human gene-environment interactions has identified a functional polymorphism in the promoter region of the gene for the serotonin transporter which appears to moderate the influence of stressful life events on the development of depression and potential for suicide.^23,24

Environment. Similarly, a key variable in determining the clinical outcome of childhood trauma may be the developmental timing of the abuse. Women abused before age 13 are at equivalent risk for developing PTSD or major depressive disorder (MDD), whereas women abused after age 13 are more likely to develop PTSD.²⁵

Thus a major challenge in depression research is to understand the biological mechanisms that mediate the effects of trauma during development through the genetic windows of vulnerability and resilience.

Animal models of ELS have been studied to elucidate the neurobiological consequences of early life trauma in adult humans. This work has largely been performed in rodents and nonhuman primates using a variety of experimental paradigms.

Although a comprehensive review of these data is beyond the scope of this article, ELS in laboratory animals has consistently been found to produce both short- and long-term adverse neurobiological and endocrine effects as well as cognitive dysfunction and abnormal behavior.²¹ One possible mechanism mediating these effects is a persistent hyperresponsiveness of different components of the HPA axis following exposure to stress.

Studies in adult women have sought to uncover the long-term effects of ELS (prepubertal physical or sexual abuse) on reactivity of the HPA axis in response to the Trier Social Stress Test, a standardized psychosocial stress test.²⁶ It consists of the subject giving a 10-minute speech and performing a mental arithmetic task in front of a panel of stern-appearing evaluators. Variables measured include heart rate, plasma ACTH, and cortisol concentration at intervals before and after the performance component of the test. The four groups in this study included:

• women without psychiatric illness or history of ELS serving as a control group (CON)
• depressed women without a history of ELS (non-ELS/MDD)
• depressed women with a history of ELS (ELS/MDD)
• non-depressed women with a history of ELS (ELS/non-MDD).

The largest ACTH and cortisol responses and increases in heart rate following this stress exposure were seen in the ELS/MDD group. In fact, the ACTH response of these women was more than 6 times greater than that observed in the control group. The ELS/MDD group of women also had greater rates of comorbid PTSD (85%) in comparison to the other experimental groups as well.

These data are consistent with the hypothesis that ELS produces enduring sensitization of the HPA axis and autonomic nervous system response to stress. This phenomenon may constitute an important etiological element in the development of stress-related adult psychiatric illnesses such as depression or PTSD.

To further explore the hypothesis that ELS alters set points of the HPA axis, we sought to characterize the effects of standard HPA axis challenge tests (CRF stimulation test and ACTH1-24 stimulation test) in a similar population of women.²⁷ Depressed women with a history of ELS and depressed women without a history of ELS both exhibited a blunted ACTH response to infusion of exogenous CRF. Conversely, women with a history of ELS but without current depression had an increased ACTH response following CRF infusion.

With respect to the ACTH1-24 stimulation test, abused women who were not depressed had lower plasma cortisol levels at baseline and after administration of ACTH1-24. Similar to the findings of our previous study,²⁶ women with MDD and a history of ELS were more likely to report current life stress and to also have comorbid PTSD than women with ELS who were not depressed. Blunting of the ACTH response to exogenous CRF in depressed women with a history of ELS may in part be secondary to acute downregulation of pituitary CRF receptors as a result of chronic CRF hypersecretion.

More recently, Carpenter and colleagues²⁸ evaluated the relationship between the perception of ELS and CSF CRF in patients with depression and healthy control subjects. The perception of ELS predicted CSF CRF concentration independent of the presence or absence of depression. Further, and most interestingly, the developmental timing of the stress exposure was predictive of either relatively increased or decreased CSF CRF. ELS before age 6 was associated with elevated CSF CRF, whereas perinatal and preteen exposure to stressful events was associated with decreased CSF CRF.

Brain structure changes? In addition to the neuroendocrine changes observed in patients with ELS, there is evidence that ELS may also alter brain structure. Reduced hippocampal volume is found in some but not all patients with unipolar depression.²⁹ In patients with a history of depression who also have hippocampal atrophy, the extent of atrophy is greater in patients with higher total lifetime duration of depression.^30,31

Patients with ELS also have been found to have decreased hippocampal volume.^32,33 However, previous structural imaging studies have not controlled for the presence of ELS when attempting to determine the relationship between depression and structural changes in the hippocampus, and this methodologic confound may explain in part the inconsistent relationship between altered hippocampal volume and depression.

To evaluate this hypothesis, hippocampal volume was measured in depressed women with and without a history of ELS and in a control group of women. Reduced hippocampal volume was found to occur solely in depressed women with a history of ELS. Depressed women without ELS and women from the control group had similar hippocampal volumes.³⁴ These data suggest that previous reports of reduced hippocampal size in patients with depression may in fact be related to a history of ELS rather than depression.

Treatment implications

The data discussed in this paper indicate that patients with depression and a history of ELS may constitute a unique subgroup among depressed patients as a whole. A growing body of evidence suggests that depressed patients with ELS may also be unique with respect to their response to treatment.

ELS has been found to impact the clinical response of patients to pharmacotherapy with either dysthymia or depression.^35,36 Further, patients with depression and a history of ELS have been reported to exhibit increased rates of relapse following treatment of depression.³⁷ The course of depression in individuals with ELS is often characterized by chronicity.

ELS and therapeutic response, Recently, our group has sought to determine whether ELS in patients with chronic depression moderates their response to pharmacotherapy or psychotherapy.³⁸ In this study, data from a large multicenter trial³⁹ originally designed to compare the relative efficacy of pharmacotherapy (nefazodone), psychotherapy (Cognitive Behavioral Analysis System of Psychotherapy), or their combination in the treatment of chronic depression was reanalyzed by stratifying patients based on the presence or absence of ELS. In the overall sample of patients with chronic depression, psychotherapy and pharmacotherapy were comparable in efficacy but significantly less effective than their combination.

ELS in chronically depressed patients was highly prevalent. Approximately one-third experienced loss of a parent before age 15, 45% experienced childhood physical abuse, 16% experienced childhood sexual abuse, and 10% experienced neglect. Most significantly, depressed patients with a history of ELS had a superior response to psychotherapy alone compared with antidepressant monotherapy. In addition, combination therapy was only slightly more effective than psychotherapy alone in the group of depressed patients with ELS.

These data suggest that ELS is common in the population of patients with chronic depression and that psychotherapy is a critical element in the treatment of depressed patients with ELS⁴⁰ (Box). However, it will be important in future studies to ascertain whether the differences in treatment response for psychotherapy compared with antidepressant in patients with ELS and depression are able to be replicated with the SSRI class of antidepressants.

BOX

Related resources

• Depression and Bipolar Support Alliance. www.dbsalliance.org.
• National Clearinghouse on Child Abuse and Neglect. http://nccanch.acf.hhs.gov.
• Charney DS, Nemeroff CB. The peace of mind prescription: An authoritative guide to finding the most effective treatment for anxiety and depression. Boston: Houghton Mifflin, 2004.

Drug brand name

• Nefazodone • Serzone

Disclosure

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

Dr. Nemeroff receives research grants from or is a consultant/speaker for Abbott Laboratories, Acadia Pharmaceuticals, American Foundation for Suicide Prevention, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Corcept Therapeutics, Cyberonics, Cypress Biosciences, Eli Lilly and Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co., Neurocrine Biosciences, Otsuka Inc., Pfizer Inc., Sanofi Aventis, and Wyeth.

Acknowledgement

Supported by NIH MH-42088, MH-52899 (CBN), and NIH NCRRM01-RR00039 to Emory University.

Sadly, parental neglect and child abuse are very common in the United States and worldwide. Patients abused or exploited in childhood, who experience neglect or the loss of a parent during childhood, are haunted by these experiences.

Considerable evidence from laboratory animal and clinical studies indicate that stressful or traumatic events early in development have long-lasting effects on brain development. In particular, the neural and endocrine systems mediating the response to stress exhibit persistent alterations after adverse childhood events.

Clinically, patients with a history of childhood trauma often struggle with variable symptom complexes including both depression and anxiety. In this article, we review evidence that depression in patients with a history of early life stress (ELS) is biologically and clinically distinct from depression in patients without childhood abuse or neglect.

Data linking ELS to depression

Conservative estimates suggest that every year in the United States more than 1 million children are exposed to sexual or physical abuse or severe neglect.¹ Unfortunately, this is only the tip of the iceberg. Emotional abuse is by definition comorbid with sexual and physical abuse and may occur alone at even higher rates.

Psychiatric sequelae of child abuse have been studied in adult survivors in considerable detail (Table). Women abused as children report greater numbers of depression, anxiety, somatic, and substance abuse symptoms compared with women without such a history.² Not only are these women at increased risk for attempted suicide, but they attempt suicide at a rate that is proportional to the number of early life traumatic events that occurred during childhood.³ Men also are at increased risk for depression in the wake of child abuse.⁴

Sexual abuse in particular is a marker of especially severe childhood trauma. Depressed women who were sexually abused as children report more childhood physical abuse, childhood emotional abuse, parental conflict, and an earlier onset of depression than depressed women without a history of sexual abuse.⁵

Finally, recent data drawn from the National Comorbidity Survey suggest that child abuse and neglect may independently elevate risk for several stress-related diseases including cardiac disease, peptic ulcer, autoimmune disease, diabetes mellitus, and lung disease.⁶

Table

Early life stress as a risk factor for mood and anxiety disorders

Depression and the biology of stress

Preclinical research using laboratory animals and clinical research with humans has provided significant insight into the relationship between the pathophysiology of depression and the neurobiology of stress. A burgeoning database suggests that disruption of the neural systems mediating the stress response plays a significant role in the etiology of certain forms of depression and anxiety.⁷ Much of this work has focused on the preeminent role of corticotropin-releasing factor (CRF) in this process (Figure).

CRF is one of the principal mediators of the mammalian stress response. One CRF system is composed of neurons of the paraventricular nuclei of the hypothalamus that project nerve terminals to the median eminence, where they secrete CRF into the hypophyseal portal system. CRF is then transported within the portal system to the anterior pituitary where it acts on corticotrophs to increase adrenocorticotrophic hormone (ACTH) secretion, thereby controlling hypothalamic-pituitary-adrenal (HPA) axis activity.⁸ CRF is also found in extrahypothalamic brain areas where it functions, in concert with the hypothalamic CRF system, as a neurotransmitter in coordinating the behavioral, autonomic, and immune responses to stress.⁹

Direct central nervous system (CNS) administration of CRF in laboratory animals, typically rodents or nonhuman primates, results in activation of the autonomic nervous system leading to elevation of peripheral catecholamines, modification of gastrointestinal activity, increased heart rate and increased blood pressure. In addition, changes in behavior similar to those observed in human depression occur, including disturbed sleep patterns, reduced food intake, decreased reproductive behavior, and enhanced fear conditioning.^10,11

In humans, elevated CRF concentrations are found in the cerebrospinal fluid (CSF) of patients with depression^12,13 and of combat veterans with posttraumatic stress disorder (PTSD).^14,15 Further, postmortem studies of suicide victims have revealed decreased density of CRF receptors in the frontal cortex,¹⁶ decreased expression of CRF receptor mRNA and increased CRF concentrations in the frontal cortex when compared with controls,¹⁷ and increased concentrations of cisternal CSF CRF.¹⁸ Collectively, these clinical data are consistent with the hypothesis that CRF is chronically hypersecreted in patients with depression or PTSD.

Figure Biological and behavioral effects of chronic CRF hypersecretion

A distinct ‘ELS depression’?

Depression has a complex etiology based on interacting contributions from genes and the environment¹⁹ that may ultimately result in biologically and clinically distinct forms of depression.²⁰ Exposure to stress, particularly during neurobiologically vulnerable periods of development, may be one means whereby the environment influences the development of depression in genetically susceptible individuals.²¹

Heredity. Kendler and colleagues²² studied 1,404 female adult twins and observed that childhood sexual abuse was associated with both an increased risk for major depression and a marked increased sensitivity to the depressogenic effects of stressful life events. Moreover, research in human gene-environment interactions has identified a functional polymorphism in the promoter region of the gene for the serotonin transporter which appears to moderate the influence of stressful life events on the development of depression and potential for suicide.^23,24

Environment. Similarly, a key variable in determining the clinical outcome of childhood trauma may be the developmental timing of the abuse. Women abused before age 13 are at equivalent risk for developing PTSD or major depressive disorder (MDD), whereas women abused after age 13 are more likely to develop PTSD.²⁵

Thus a major challenge in depression research is to understand the biological mechanisms that mediate the effects of trauma during development through the genetic windows of vulnerability and resilience.

Animal models of ELS have been studied to elucidate the neurobiological consequences of early life trauma in adult humans. This work has largely been performed in rodents and nonhuman primates using a variety of experimental paradigms.

Although a comprehensive review of these data is beyond the scope of this article, ELS in laboratory animals has consistently been found to produce both short- and long-term adverse neurobiological and endocrine effects as well as cognitive dysfunction and abnormal behavior.²¹ One possible mechanism mediating these effects is a persistent hyperresponsiveness of different components of the HPA axis following exposure to stress.

Studies in adult women have sought to uncover the long-term effects of ELS (prepubertal physical or sexual abuse) on reactivity of the HPA axis in response to the Trier Social Stress Test, a standardized psychosocial stress test.²⁶ It consists of the subject giving a 10-minute speech and performing a mental arithmetic task in front of a panel of stern-appearing evaluators. Variables measured include heart rate, plasma ACTH, and cortisol concentration at intervals before and after the performance component of the test. The four groups in this study included:

• women without psychiatric illness or history of ELS serving as a control group (CON)
• depressed women without a history of ELS (non-ELS/MDD)
• depressed women with a history of ELS (ELS/MDD)
• non-depressed women with a history of ELS (ELS/non-MDD).

The largest ACTH and cortisol responses and increases in heart rate following this stress exposure were seen in the ELS/MDD group. In fact, the ACTH response of these women was more than 6 times greater than that observed in the control group. The ELS/MDD group of women also had greater rates of comorbid PTSD (85%) in comparison to the other experimental groups as well.

These data are consistent with the hypothesis that ELS produces enduring sensitization of the HPA axis and autonomic nervous system response to stress. This phenomenon may constitute an important etiological element in the development of stress-related adult psychiatric illnesses such as depression or PTSD.

To further explore the hypothesis that ELS alters set points of the HPA axis, we sought to characterize the effects of standard HPA axis challenge tests (CRF stimulation test and ACTH1-24 stimulation test) in a similar population of women.²⁷ Depressed women with a history of ELS and depressed women without a history of ELS both exhibited a blunted ACTH response to infusion of exogenous CRF. Conversely, women with a history of ELS but without current depression had an increased ACTH response following CRF infusion.

With respect to the ACTH1-24 stimulation test, abused women who were not depressed had lower plasma cortisol levels at baseline and after administration of ACTH1-24. Similar to the findings of our previous study,²⁶ women with MDD and a history of ELS were more likely to report current life stress and to also have comorbid PTSD than women with ELS who were not depressed. Blunting of the ACTH response to exogenous CRF in depressed women with a history of ELS may in part be secondary to acute downregulation of pituitary CRF receptors as a result of chronic CRF hypersecretion.

More recently, Carpenter and colleagues²⁸ evaluated the relationship between the perception of ELS and CSF CRF in patients with depression and healthy control subjects. The perception of ELS predicted CSF CRF concentration independent of the presence or absence of depression. Further, and most interestingly, the developmental timing of the stress exposure was predictive of either relatively increased or decreased CSF CRF. ELS before age 6 was associated with elevated CSF CRF, whereas perinatal and preteen exposure to stressful events was associated with decreased CSF CRF.

Brain structure changes? In addition to the neuroendocrine changes observed in patients with ELS, there is evidence that ELS may also alter brain structure. Reduced hippocampal volume is found in some but not all patients with unipolar depression.²⁹ In patients with a history of depression who also have hippocampal atrophy, the extent of atrophy is greater in patients with higher total lifetime duration of depression.^30,31

Patients with ELS also have been found to have decreased hippocampal volume.^32,33 However, previous structural imaging studies have not controlled for the presence of ELS when attempting to determine the relationship between depression and structural changes in the hippocampus, and this methodologic confound may explain in part the inconsistent relationship between altered hippocampal volume and depression.

To evaluate this hypothesis, hippocampal volume was measured in depressed women with and without a history of ELS and in a control group of women. Reduced hippocampal volume was found to occur solely in depressed women with a history of ELS. Depressed women without ELS and women from the control group had similar hippocampal volumes.³⁴ These data suggest that previous reports of reduced hippocampal size in patients with depression may in fact be related to a history of ELS rather than depression.

Treatment implications

The data discussed in this paper indicate that patients with depression and a history of ELS may constitute a unique subgroup among depressed patients as a whole. A growing body of evidence suggests that depressed patients with ELS may also be unique with respect to their response to treatment.

ELS has been found to impact the clinical response of patients to pharmacotherapy with either dysthymia or depression.^35,36 Further, patients with depression and a history of ELS have been reported to exhibit increased rates of relapse following treatment of depression.³⁷ The course of depression in individuals with ELS is often characterized by chronicity.

ELS and therapeutic response, Recently, our group has sought to determine whether ELS in patients with chronic depression moderates their response to pharmacotherapy or psychotherapy.³⁸ In this study, data from a large multicenter trial³⁹ originally designed to compare the relative efficacy of pharmacotherapy (nefazodone), psychotherapy (Cognitive Behavioral Analysis System of Psychotherapy), or their combination in the treatment of chronic depression was reanalyzed by stratifying patients based on the presence or absence of ELS. In the overall sample of patients with chronic depression, psychotherapy and pharmacotherapy were comparable in efficacy but significantly less effective than their combination.

ELS in chronically depressed patients was highly prevalent. Approximately one-third experienced loss of a parent before age 15, 45% experienced childhood physical abuse, 16% experienced childhood sexual abuse, and 10% experienced neglect. Most significantly, depressed patients with a history of ELS had a superior response to psychotherapy alone compared with antidepressant monotherapy. In addition, combination therapy was only slightly more effective than psychotherapy alone in the group of depressed patients with ELS.

These data suggest that ELS is common in the population of patients with chronic depression and that psychotherapy is a critical element in the treatment of depressed patients with ELS⁴⁰ (Box). However, it will be important in future studies to ascertain whether the differences in treatment response for psychotherapy compared with antidepressant in patients with ELS and depression are able to be replicated with the SSRI class of antidepressants.

BOX

Related resources

• Depression and Bipolar Support Alliance. www.dbsalliance.org.
• National Clearinghouse on Child Abuse and Neglect. http://nccanch.acf.hhs.gov.
• Charney DS, Nemeroff CB. The peace of mind prescription: An authoritative guide to finding the most effective treatment for anxiety and depression. Boston: Houghton Mifflin, 2004.

Drug brand name

• Nefazodone • Serzone

Disclosure

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

Dr. Nemeroff receives research grants from or is a consultant/speaker for Abbott Laboratories, Acadia Pharmaceuticals, American Foundation for Suicide Prevention, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Corcept Therapeutics, Cyberonics, Cypress Biosciences, Eli Lilly and Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co., Neurocrine Biosciences, Otsuka Inc., Pfizer Inc., Sanofi Aventis, and Wyeth.

Acknowledgement

Supported by NIH MH-42088, MH-52899 (CBN), and NIH NCRRM01-RR00039 to Emory University.

Several years ago, actor Tom Cruise denounced psychiatrists’ use of antidepressants and methylphenidate in children and adults. I took his comments as innocent expressions of ignorance about a specialty that takes years of study to understand.

Recently, however, Cruise criticized actress Brooke Shields for taking antidepressants for her postpartum depression. He then verbally attacked NBC television’s Today show host Matt Lauer, who said he knows people who have benefited from using methylphenidate.

I think Cruise is venting his psychological issues in public but using the wrong venue. A well-known country music singer interviewed by CNN’s Anderson Cooper also suggested that Cruise discuss his own emotional issues instead of chastising the people who could help him. The singer told Cooper how antidepressants saved her career and possibly her life.

If your patients won’t try medication after Cruise’s diatribes, I offer these two examples:

• A 76-year-old woman refused to eat for fear of being poisoned by her relatives. She spent all day in bed and demanded to see her lawyer to change her power of attorney. I started her on olanzapine, 5 mg/d, which increases appetite as a side effect. Three days later, she was eating and sleeping normally and attending physical therapy sessions.
  
• An 8-year-old boy with obsessive-compulsive disorder was using three or four rolls of toilet paper per day and taking 1-hour showers to make sure he didn’t smell. After 2 weeks of sertraline, 50 mg/d, and behavior modification by a psychotherapist, his behavior improved dramatically.
  

I would love to hear how Cruise and others who stigmatize psychotropic use dispute how the medications improved these patients’ quality of life. Shields offered this testimony:

“To suggest that I was wrong to take drugs to deal with my depression, and that instead I should have taken vitamins and exercised, shows an utter lack of understanding about postpartum depression and childbirth in general,” Shields wrote in The New York Times. “If any good can come of (Cruise’s comments), let’s hope (they call) much-needed attention to a serious disease.”

Manuel Mota-Castillo, MD
Medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services, Lake Mary, FL

Several years ago, actor Tom Cruise denounced psychiatrists’ use of antidepressants and methylphenidate in children and adults. I took his comments as innocent expressions of ignorance about a specialty that takes years of study to understand.

Recently, however, Cruise criticized actress Brooke Shields for taking antidepressants for her postpartum depression. He then verbally attacked NBC television’s Today show host Matt Lauer, who said he knows people who have benefited from using methylphenidate.

I think Cruise is venting his psychological issues in public but using the wrong venue. A well-known country music singer interviewed by CNN’s Anderson Cooper also suggested that Cruise discuss his own emotional issues instead of chastising the people who could help him. The singer told Cooper how antidepressants saved her career and possibly her life.

If your patients won’t try medication after Cruise’s diatribes, I offer these two examples:

• A 76-year-old woman refused to eat for fear of being poisoned by her relatives. She spent all day in bed and demanded to see her lawyer to change her power of attorney. I started her on olanzapine, 5 mg/d, which increases appetite as a side effect. Three days later, she was eating and sleeping normally and attending physical therapy sessions.
  
• An 8-year-old boy with obsessive-compulsive disorder was using three or four rolls of toilet paper per day and taking 1-hour showers to make sure he didn’t smell. After 2 weeks of sertraline, 50 mg/d, and behavior modification by a psychotherapist, his behavior improved dramatically.
  

I would love to hear how Cruise and others who stigmatize psychotropic use dispute how the medications improved these patients’ quality of life. Shields offered this testimony:

“To suggest that I was wrong to take drugs to deal with my depression, and that instead I should have taken vitamins and exercised, shows an utter lack of understanding about postpartum depression and childbirth in general,” Shields wrote in The New York Times. “If any good can come of (Cruise’s comments), let’s hope (they call) much-needed attention to a serious disease.”

Manuel Mota-Castillo, MD
Medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services, Lake Mary, FL

Several years ago, actor Tom Cruise denounced psychiatrists’ use of antidepressants and methylphenidate in children and adults. I took his comments as innocent expressions of ignorance about a specialty that takes years of study to understand.

Recently, however, Cruise criticized actress Brooke Shields for taking antidepressants for her postpartum depression. He then verbally attacked NBC television’s Today show host Matt Lauer, who said he knows people who have benefited from using methylphenidate.

I think Cruise is venting his psychological issues in public but using the wrong venue. A well-known country music singer interviewed by CNN’s Anderson Cooper also suggested that Cruise discuss his own emotional issues instead of chastising the people who could help him. The singer told Cooper how antidepressants saved her career and possibly her life.

If your patients won’t try medication after Cruise’s diatribes, I offer these two examples:

• A 76-year-old woman refused to eat for fear of being poisoned by her relatives. She spent all day in bed and demanded to see her lawyer to change her power of attorney. I started her on olanzapine, 5 mg/d, which increases appetite as a side effect. Three days later, she was eating and sleeping normally and attending physical therapy sessions.
  
• An 8-year-old boy with obsessive-compulsive disorder was using three or four rolls of toilet paper per day and taking 1-hour showers to make sure he didn’t smell. After 2 weeks of sertraline, 50 mg/d, and behavior modification by a psychotherapist, his behavior improved dramatically.
  

I would love to hear how Cruise and others who stigmatize psychotropic use dispute how the medications improved these patients’ quality of life. Shields offered this testimony:

“To suggest that I was wrong to take drugs to deal with my depression, and that instead I should have taken vitamins and exercised, shows an utter lack of understanding about postpartum depression and childbirth in general,” Shields wrote in The New York Times. “If any good can come of (Cruise’s comments), let’s hope (they call) much-needed attention to a serious disease.”

Manuel Mota-Castillo, MD
Medical director
The Grove Academy, Sanford, FL
and Lake Mary Psychiatric Services, Lake Mary, FL

One in five of your patients could suffer a heart attack in the near future—unless you take steps to ensure their heart health.

Psychiatric patients have more modifiable risk factors for coronary artery disease (CAD) compared with the general population.^{When depression treatment goes nowhere,” Current Psychiatry, August 2005.)}

To help keep you abreast of constantly changing guidelines and strategies for recognizing and minimizing CAD risk, this article discusses:

• preventive and diagnostic guidelines for managing hypertension, diabetes, and dyslipidemia
  
• practical advice on convincing at-risk patients to adopt a healthier lifestyle and have a primary care doctor monitor their health.
  

Case: cigarettes and supersizing

Mr. H, age 54, is receiving cognitive-behavioral therapy for mild depression. He has been smoking one pack of cigarettes per day for 20 years and has never seriously considered quitting.

The patient, a school teacher, says his “busy schedule” keeps him from exercising and eating properly; he eats fast-food hamburgers and fries approximately five times per week. His father had a heart attack at age 52 and died in his sleep 10 years later.

Mr. H says he feels fine and has never seen a physician other than his psychiatrist. He is reluctant to see a primary care physician for a check-up and, because he is asymptomatic, has no incentive to do so. The psychiatrist thus decides to do a routine examination.

Blood pressure is 148/86; other vital signs are normal. Mr. H’s waist size is 42 inches, he weighs 242 lbs, and his body mass index (BMI) is 34 kg/m², indicating clinical obesity. Cardiovascular, pulmonary, and abdominal exams are unremarkable.

Discussion. Mr. H is at high risk of a myocardial ischemic event in the near future. He has six risk factors for CAD (Table 1)—four of which are modifiable:

• family history
  
• age
  
• current cigarette use
  
• provisional hypertension diagnosis
  
• obesity
  
• physical inactivity.
  

Table 1

Risk factors for coronary artery disease

Tools for assessing risk

The lifetime risk at age 40 for developing CAD is 49% and 32% in men and women, respectively.⁶

The National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel) has focused on decreasing heart disease incidence by educating patients and providers. Preventive strategies and standards of care have changed several times over the past decade; the Adult Treatment Panel (ATP III) was last revised in July 2004.⁷

The American College of Cardiology and American Heart Association both endorse the modified Framingham/ATP III scale to measure CAD risk (see Related resources). Although this somewhat tedious point system has limitations, it can precisely calculate coronary risk across 10 years.⁸ Variables not included in the scoring system—such as C-reactive protein, homocysteine, and postmenopausal state—may be clinically significant and should be gauged separately.

An easier-to-use alternative, the ATP III “core risk factors” scale, estimates hypertension, hypercholesterolemia, family history, current cigarette smoking, and age as low, intermediate, or high (“risk equivalent”) risks (Table 1).⁸ Psychiatrists can quickly obtain this information from a brief history, blood pressure assessment, and relatively inexpensive lab studies.

Generally, the more risk factors present, the higher the risk of having a major coronary event. Presence of ≥ 2 risk factors signals intermediate or high risk and necessitates referral to a primary care doctor for monitoring.

Patients with a cardiac “risk equivalent” face a >20% risk of having a cardiac ischemic event within 10 years⁸ (Table 2). Examples of risk equivalents include diabetes or significant vascular disease in any artery.

“Non-core” variables. Also consider certain “non-core” variables—such as pre-existing psychiatric illness—when estimating clinical risk for heart disease. Depression, anxiety, and stress are correlated with an increase in pro-inflammatory markers such as C-reactive protein and predispose patients to CAD.^11,12 Depression has repeatedly been shown to increase morbidity and mortality two- to four-fold after myocardial infarction (MI).^9,13,14 Interestingly, however, depression treatment after an acute coronary event does not clearly decrease mortality.¹⁵ Although prospective, randomized studies are lacking, mood and anxiety disorder treatment is presumed to help prevent CAD development.¹⁶

Table 2

Risk equivalents for CAD*

Recognizing cad risk

At what point do hypertension and dyslipidemia become risk factors for CAD? When and how often should patients be screened for diabetes mellitus?

Hypertension is one of the most common and deadly CAD risk factors, affecting 50 million Americans.¹⁰ Although hypertension awareness and treatment have improved, only 35% of adults have “controlled” blood pressure (

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), normalizing blood pressure can reduce stroke incidence by 35% and MI by 25%, respectively. JNC 7, however, also found that 90% of persons who are normotensive at age 55 eventually develop hypertension.¹⁰

Based on these findings, JNC 7 in 2003 drastically changed the standard of care for diagnosing hypertension. JNC 7 defines normal blood pressure as

• systolic blood pressure 120 to 139 mm Hg
  
• diastolic blood pressure 80 to 89 mm Hg (Table 3).
  

Patients with diabetes mellitus or chronic kidney disease are considered hypertensive with blood pressure >130 mm Hg systolic and/or >80 mm Hg diastolic.

As with Mr. H, a blood pressure check is imperative for patients who have rarely or never seen a primary care physician in recent years. The U.S. Preventive Services Task Force strongly recommends measuring blood pressure during a routine medical evaluation at least every 2 years. A second abnormal reading at a separate visit at any time should prompt a hypertension diagnosis. Once diagnosed with hypertension, patients should be treated and checked monthly until stable, then monitored every 3 to 6 months indefinitely.¹⁰

If you cannot measure blood pressure in the office, urge patients to use an over-the-counter blood pressure measuring device and refer them to a primary care physician. Check the patient’s self-test reading for accuracy against a clinician’s measurement.

Diabetes is now considered a risk equivalent for CAD development.⁸ Patients diagnosed with diabetes are extremely likely to have established vascular disease,⁸ which predisposes them to MI, stroke, kidney disease, blindness, and lower-extremity amputations.¹⁷ Those with type 1 diabetes usually present with acute symptoms—including polyuria, polydipsia, weight loss, malaise, dry mouth, and blurred vision—and are readily diagnosed with elevated plasma glucose.

Screening for diabetes is critical because one-third of patients with the disease are undiagnosed. Also, more than 90% of patients with diabetes are non-insulin-dependent (type 2) and are asymptomatic early in the disease course.

No data definitively show benefits from screening asymptomatic adults. Recently revised diagnostic criteria for diabetes, however, call for re-testing asymptomatic patients who were found to have normal fasting plasma glucose (FPG) levels and were considered “free” of diabetes. The American Diabetes Association recommends measuring FPG after no caloric intake for ≥ 8 hours for asymptomatic patients.

FPG measurement is cost-effective and generally more convenient than other diabetes tests.¹⁷ Expert consensus strongly suggests checking FPG every 3 years beginning at age 45:¹⁷

• FPG
• FPG 100 to 125 mg/dL suggests prediabetes or impaired fasting glucose
  
• FPG ≥ 126 mg/dL demands a provisional diabetes diagnosis and a follow-up test on another day to confirm the diagnosis.
  

• comorbid cardiac risk factors
  
• history of polycystic ovary disease
  
• a first-degree relative with diabetes
  
• habitual inactivity
  
• or FPG 100 to 125 mg/dL.
  

Do not base diabetes diagnosis on glycosylated hemoglobin measurements, as this test can produce false-negative results in patients with new-onset diabetes.

Dyslipidemia. Every 10% reduction in serum cholesterol reduces cardiovascular mortality by 10% to 15%.¹⁹ Data from the large, prospective Framingham heart study show a 25% increase in MIs with each 5-mg/dL decrease in high-density lipoprotein cholesterol (HDL) below the age-based median for men and women.²⁰ Serum triglycerides >150 mg/dL clearly predict future CAD and increase the likelihood of abnormally low HDL.

Every 30-mg/dL increase in low-density lipoprotein cholesterol (LDL) raises the relative risk for CAD by 30%.⁷ ATP III classifies LDL as the “primary target of cholesterol-lowering therapy.”⁸Table 4 lists LDL target levels based on other CAD risk factors.

Check fasting lipid profile or serum cholesterol, LDL, HDL, and triglycerides beginning at age 20 and about every 5 years thereafter.⁸ Total cholesterol

Table 3

JNC 7: What blood pressure readings mean

Acceptable LDL cholesterol levels for adults based on CAD risk

Addressing smoking, obesity

Smoking. Before trying nicotine patches or bupropion, Mr. H should realistically contemplate his risks with continued smoking; if he doesn’t want to stop, periodically encourage him to reconsider.¹⁰ Most people know the dangers of smoking but few understand that complete cessation for 1 to 2 years often nearly reverses cardiovascular disease.²¹

Obesity and lack of exercise go hand in hand. Reducing Mr. H’s waist size to 2 is a reasonable short-term goal. To that end, encourage him to:

• decrease his number of weekly fast-food meals from five to three, with an eventual goal of one per week. As an alternative, microwaveable, low-calorie meals—each with at least two servings of fruits or vegetables—can be prepared at home or work.
  
• walk 30 minutes three times weekly and progress to 1 hour five times weekly over 6 months. As with any exercise program, remind Mr. H to “start low and go slow.”
  

The patient’s role in treatment. Patients often feel overwhelmed after getting large amounts of information on CAD risk and may feel hopeless and unenthusiastic about improving their physical health. Work with the primary care doctor to emphasize a patient care plan that clearly defines easily attainable, step-by-step goals. Make sure the patient agrees to these goals.

Case continued: no more supersizing

Mr. H now understands the importance of minimizing his CAD risk and realizes that CAD and many associated risk factors are asymptomatic in the early stages of development.

With help from his doctors, Mr. H quit smoking. He also became more mindful of his caloric intake and the types of foods he was eating. He advanced from briskly walking 30 minutes three times per week to slow jogging 40 minutes five times weekly. He still eats at fast-food restaurants but usually orders broiled chicken, salads, or the occasional burger.

Related resources

• National Cholesterol Education Program. CAD risk assessment tool and ATP III guidelines. www.nhlbi.nih.gov/guidelines/cholesterol/.
  
• U.S. Preventive Services Task Force preventive guidelines. www.ahrq.gov/clinic/uspstfix.htm.
  
• National Heart, Lung, and Blood Institute. Calculate your body mass index. http://nhlbisupport.com/bmi/.
  
• American Heart Association. www.americanheart.org.
  

One in five of your patients could suffer a heart attack in the near future—unless you take steps to ensure their heart health.

Psychiatric patients have more modifiable risk factors for coronary artery disease (CAD) compared with the general population.^{When depression treatment goes nowhere,” Current Psychiatry, August 2005.)}

To help keep you abreast of constantly changing guidelines and strategies for recognizing and minimizing CAD risk, this article discusses:

• preventive and diagnostic guidelines for managing hypertension, diabetes, and dyslipidemia
  
• practical advice on convincing at-risk patients to adopt a healthier lifestyle and have a primary care doctor monitor their health.
  

Case: cigarettes and supersizing

Mr. H, age 54, is receiving cognitive-behavioral therapy for mild depression. He has been smoking one pack of cigarettes per day for 20 years and has never seriously considered quitting.

The patient, a school teacher, says his “busy schedule” keeps him from exercising and eating properly; he eats fast-food hamburgers and fries approximately five times per week. His father had a heart attack at age 52 and died in his sleep 10 years later.

Mr. H says he feels fine and has never seen a physician other than his psychiatrist. He is reluctant to see a primary care physician for a check-up and, because he is asymptomatic, has no incentive to do so. The psychiatrist thus decides to do a routine examination.

Blood pressure is 148/86; other vital signs are normal. Mr. H’s waist size is 42 inches, he weighs 242 lbs, and his body mass index (BMI) is 34 kg/m², indicating clinical obesity. Cardiovascular, pulmonary, and abdominal exams are unremarkable.

Discussion. Mr. H is at high risk of a myocardial ischemic event in the near future. He has six risk factors for CAD (Table 1)—four of which are modifiable:

• family history
  
• age
  
• current cigarette use
  
• provisional hypertension diagnosis
  
• obesity
  
• physical inactivity.
  

Table 1

Risk factors for coronary artery disease

Tools for assessing risk

The lifetime risk at age 40 for developing CAD is 49% and 32% in men and women, respectively.⁶

The National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel) has focused on decreasing heart disease incidence by educating patients and providers. Preventive strategies and standards of care have changed several times over the past decade; the Adult Treatment Panel (ATP III) was last revised in July 2004.⁷

The American College of Cardiology and American Heart Association both endorse the modified Framingham/ATP III scale to measure CAD risk (see Related resources). Although this somewhat tedious point system has limitations, it can precisely calculate coronary risk across 10 years.⁸ Variables not included in the scoring system—such as C-reactive protein, homocysteine, and postmenopausal state—may be clinically significant and should be gauged separately.

An easier-to-use alternative, the ATP III “core risk factors” scale, estimates hypertension, hypercholesterolemia, family history, current cigarette smoking, and age as low, intermediate, or high (“risk equivalent”) risks (Table 1).⁸ Psychiatrists can quickly obtain this information from a brief history, blood pressure assessment, and relatively inexpensive lab studies.

Generally, the more risk factors present, the higher the risk of having a major coronary event. Presence of ≥ 2 risk factors signals intermediate or high risk and necessitates referral to a primary care doctor for monitoring.

Patients with a cardiac “risk equivalent” face a >20% risk of having a cardiac ischemic event within 10 years⁸ (Table 2). Examples of risk equivalents include diabetes or significant vascular disease in any artery.

“Non-core” variables. Also consider certain “non-core” variables—such as pre-existing psychiatric illness—when estimating clinical risk for heart disease. Depression, anxiety, and stress are correlated with an increase in pro-inflammatory markers such as C-reactive protein and predispose patients to CAD.^11,12 Depression has repeatedly been shown to increase morbidity and mortality two- to four-fold after myocardial infarction (MI).^9,13,14 Interestingly, however, depression treatment after an acute coronary event does not clearly decrease mortality.¹⁵ Although prospective, randomized studies are lacking, mood and anxiety disorder treatment is presumed to help prevent CAD development.¹⁶

Table 2

Risk equivalents for CAD*

Recognizing cad risk

At what point do hypertension and dyslipidemia become risk factors for CAD? When and how often should patients be screened for diabetes mellitus?

Hypertension is one of the most common and deadly CAD risk factors, affecting 50 million Americans.¹⁰ Although hypertension awareness and treatment have improved, only 35% of adults have “controlled” blood pressure (

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), normalizing blood pressure can reduce stroke incidence by 35% and MI by 25%, respectively. JNC 7, however, also found that 90% of persons who are normotensive at age 55 eventually develop hypertension.¹⁰

Based on these findings, JNC 7 in 2003 drastically changed the standard of care for diagnosing hypertension. JNC 7 defines normal blood pressure as

• systolic blood pressure 120 to 139 mm Hg
  
• diastolic blood pressure 80 to 89 mm Hg (Table 3).
  

Patients with diabetes mellitus or chronic kidney disease are considered hypertensive with blood pressure >130 mm Hg systolic and/or >80 mm Hg diastolic.

As with Mr. H, a blood pressure check is imperative for patients who have rarely or never seen a primary care physician in recent years. The U.S. Preventive Services Task Force strongly recommends measuring blood pressure during a routine medical evaluation at least every 2 years. A second abnormal reading at a separate visit at any time should prompt a hypertension diagnosis. Once diagnosed with hypertension, patients should be treated and checked monthly until stable, then monitored every 3 to 6 months indefinitely.¹⁰

If you cannot measure blood pressure in the office, urge patients to use an over-the-counter blood pressure measuring device and refer them to a primary care physician. Check the patient’s self-test reading for accuracy against a clinician’s measurement.

Diabetes is now considered a risk equivalent for CAD development.⁸ Patients diagnosed with diabetes are extremely likely to have established vascular disease,⁸ which predisposes them to MI, stroke, kidney disease, blindness, and lower-extremity amputations.¹⁷ Those with type 1 diabetes usually present with acute symptoms—including polyuria, polydipsia, weight loss, malaise, dry mouth, and blurred vision—and are readily diagnosed with elevated plasma glucose.

Screening for diabetes is critical because one-third of patients with the disease are undiagnosed. Also, more than 90% of patients with diabetes are non-insulin-dependent (type 2) and are asymptomatic early in the disease course.

No data definitively show benefits from screening asymptomatic adults. Recently revised diagnostic criteria for diabetes, however, call for re-testing asymptomatic patients who were found to have normal fasting plasma glucose (FPG) levels and were considered “free” of diabetes. The American Diabetes Association recommends measuring FPG after no caloric intake for ≥ 8 hours for asymptomatic patients.

FPG measurement is cost-effective and generally more convenient than other diabetes tests.¹⁷ Expert consensus strongly suggests checking FPG every 3 years beginning at age 45:¹⁷

• FPG
• FPG 100 to 125 mg/dL suggests prediabetes or impaired fasting glucose
  
• FPG ≥ 126 mg/dL demands a provisional diabetes diagnosis and a follow-up test on another day to confirm the diagnosis.
  

• comorbid cardiac risk factors
  
• history of polycystic ovary disease
  
• a first-degree relative with diabetes
  
• habitual inactivity
  
• or FPG 100 to 125 mg/dL.
  

Do not base diabetes diagnosis on glycosylated hemoglobin measurements, as this test can produce false-negative results in patients with new-onset diabetes.

Dyslipidemia. Every 10% reduction in serum cholesterol reduces cardiovascular mortality by 10% to 15%.¹⁹ Data from the large, prospective Framingham heart study show a 25% increase in MIs with each 5-mg/dL decrease in high-density lipoprotein cholesterol (HDL) below the age-based median for men and women.²⁰ Serum triglycerides >150 mg/dL clearly predict future CAD and increase the likelihood of abnormally low HDL.

Every 30-mg/dL increase in low-density lipoprotein cholesterol (LDL) raises the relative risk for CAD by 30%.⁷ ATP III classifies LDL as the “primary target of cholesterol-lowering therapy.”⁸Table 4 lists LDL target levels based on other CAD risk factors.