Current Psychiatry

Delirium is a medical emergency that needs to be identified and treated vigorously. Antipsychotics—including haloperidol and atypical agents—effectively manage a wide spectrum of delirium symptoms and are an essential component in the standard multimodal approach.¹ Even so, antipsychotics are not FDA-approved for treating delirium, and evidence on their safety in medically ill patients is limited—particularly in the elderly, in whom delirium occurs most often.

The FDA has warned of increased risk of death when atypical antipsychotics are used to treat behavioral disturbances in elderly patients with dementia.² Similarly, a retrospective study of elderly patients taking antipsychotics found higher mortality rates associated with typical antipsychotics than with atypicals.³

This article discusses the risks and benefits of using antipsychotics to manage delirium. Based on the literature and clinical experience, we offer recommendations on choosing among the available agents and avoiding side effects.

A challenging diagnosis

Delirium is a neuropsychiatric syndrome precipitated by an underlying medical condition or a medication effect on the brain. Its characteristic symptoms—abrupt onset of disturbed consciousness, attention, cognition, and perception—tend to fluctuate during the day. Delirium most often occurs in elderly patients (Box)^1,4-7—particularly with dementia—but also occurs in younger patients with serious illnesses such as cancer or HIV-AIDS.

Delirium is underdiagnosed and under-treated in medical settings,^4,8 most likely because of its protean symptoms (Table 1)⁹ and fluctuating clinical findings. Neurologic abnormalities—including cortical and motor symptoms—also can occur.¹

Mortality risk. Delirium is an independent risk factor for mortality.^1,4,5 It is a marker for serious and potentially life-threatening medical problems, such as organ failure or sepsis. When antipsychotics fail to control delirium, the 3 most common reasons are:

• delirium’s etiology has not been discovered or addressed
  
• delirium’s etiology is resistant to treatment or potentially irreversible
  
• antipsychotic dosage was inadequate.
  

3 subtypes. Delirium is classified as hyperactive, hypoactive, or mixed, depending on arousal disturbance and psychomotor behavior:

• the hyperactive subtype includes hallucinations, delusions, agitation, and disorientation.
  
• the hypoactive subtype includes confusion, sedation, and decreased alertness but rarely hallucinations or delusions.¹
  

Box

Antipsychotics: Limited evidence

• identifying and eliminating contributing factors
  
• instituting nonpharmacologic interventions based on environmental strategies (Table 2)⁴
  
• providing pharmacologic interventions—primarily antipsychotics—as needed.
  

• delirium severity improved with haloperidol, chlorpromazine, olanzapine, risperidone, or quetiapine
  
• comparison trials did not identify any antipsychotic as more efficacious than another.
  

Michaud et al¹¹ reviewed guidelines, systematic reviews, randomized controlled trials, and cohort studies on delirium management. They concluded that the experts agree on 3 points:

• prevention should be emphasized
  
• atypical antipsychotics are not first-choice drugs because of data on adverse events in the elderly
  
• pharmacologic treatment is recommended when the patient’s condition prevents adequate care or puts the patient or staff at risk.
  

Conventional antipsychotics

Haloperidol, the most-studied antipsychotic in delirium treatment, often is the drug of choice because of its high potency, low sedative effect, few anticholinergic side effects, minimal cardiovascular side effects, no active metabolites, and multiple administration routes.¹

Any IV use of injectable haloperidol is off-label, however. If you choose the IV route, monitor patients carefully for cardiac arrhythmias. Haloperidol’s prescribing information carries a new warning of sudden death, QT prolongation, and torsades de pointes in patients given IV haloperidol.

Chlorpromazine. In a double-blind, randomized comparison trial of 30 hospitalized AIDS patients, our group¹² found oral and IM haloperidol (n=11) or chlorpromazine (n=13) highly effective in controlling delirium. Delirium symptoms improved significantly in both hypoactive and hyperactive subtypes with low doses of either antipsychotic (approximately 2 mg of haloperidol equivalent/day).

No patients developed dystonic or dyskinetic symptoms. Lorazepam, given to 6 patients, worsened delirium and cognitive impairment.

Table 1

Recognizing delirium: Diagnostic clinical features*

Nonpharmacologic approaches to managing delirium

Atypicals in delirium: Trial data

Risperidone. Three open-label studies of risperidone in patients with delirium reported minimal risk of sedation and EPS.^13-15

A 7-day, double-blind, flexible-dose trial of 24 patients with delirium¹⁶ found no significant difference between haloperidol (mean 1.71 mg/d) and risperidone (mean 1.02 mg/d) in clinical efficacy or response rate. The authors acknowledged, that they were unable to obtain identical-looking haloperidol and risperidone tablets for the trial.

Kim et al¹⁷ studied dopamine transporter gene polymorphism and use of haloperidol vs risperidone in 42 patients with delirium. Relatively low doses of both antipsychotics showed similar efficacy, and the authors concluded that dopamine transporter gene polymorphism did not influence delirium treatment.

Olanzapine. In an open trial of 79 inpatients with advanced cancer, olanzapine (mean 6.3 mg/d, range 2.5 to 20 mg/d) resolved delirium in 76% of patients, with no incidence of EPS.¹⁸ Age >70, history of dementia, hypoxia, cerebral metastasis, and hypoactive delirium were associated with poor response to olanzapine. This study is unique in assessing olanzapine’s efficacy in different delirium subtypes.

A prospective, randomized trial compared olanzapine (mean 4.5 mg/d, range 2.5 to 13.5 mg/d) with haloperidol (mean 6.5 mg/d, range 1 to 28 mg/d) in patients admitted with delirium to a critical care setting.¹⁹ Both treatment groups showed similar improvement over 5 days. No side effects were reported in the patients receiving olanzapine.

Ziprasidone. In the first case report in which ziprasidone was used to treat delirium,²¹ an HIV/AIDS patient was given 100 mg/d. Delirium symptoms improved, but treatment was discontinued because of side effects (hypokalemia, hypomagnesemia, premature ventricular contractions, and QT interval prolongation).

Aripiprazole. Straker et al²² reported 14 cases delirium treated with aripiprazole, which showed few side effects. Twelve patients had a ≥50% decrease in Delirium Rating Scale scores, and 13 showed improvement in Clinical Global Impression scale scores.

Clinical options

When choosing an antipsychotic to treat delirium, consider the individual patient’s risks of EPS, sedation, anticholinergic side effects, cardiac arrhythmias, and drug-drug interactions.

Haloperidol. When medication is necessary for delirium, American Psychiatric Association (APA) guidelines consider low-dose haloperidol as first-line treatment (see Related Resources). Recommended dosage is 1 to 2 mg (0.25 to 0.5 mg for the elderly) every 4 hours as needed.

Adding oral or IV lorazepam (0.5 to 1 mg every 1 to 2 hours) to haloperidol may help rapidly sedate the agitated delirious patient and minimize the risk of EPS associated with haloperidol.¹ Avoid benzodiazepine monotherapy unless delirium is related to alcohol or benzodiazepine withdrawal.

Chlorpromazine. We have successfully used oral or IV chlorpromazine (12.5 to 50 mg every 4 to 12 hours) instead of haloperidol plus lorazepam when increased sedation was required, especially:

• in the ICU, where close blood pressure monitoring was feasible
  
• for severe agitation in terminally ill patients to decrease distress for the patient, family and staff.
  

Atypical antipsychotics also may be used to treat delirium, as supported by the literature. Recommended dosing, available routes administration routes, and clinical comments are summarized in Table 3.²³

Table 3

Recommended antipsychotic dosing for delirium*

Managing adverse effects

Reassess patients frequently during a delirium episode to adjust the antipsychotic dose, search for underlying causes, and monitor for side effects (Table 4). In frail elderly patients, start with approximately one-half the recommended initial dose to reduce the side effect risk.

Antipsychotics may not be appropriate in certain populations with delirium, particularly in patients with:

• dementia of Lewy body type or Parkinson’s disease dementia
  
• stroke
  
• history of adverse reactions to antipsychotics.
  

Although the FDA advisory did not apply to typical antipsychotics, Wang et al³—in a retrospective cohort of nearly 23,000 patients age >65—found statistically significant higher mortality rates with typical vs atypical antipsychotics. The increased mortality risk with the typical agents was seen whether or not patients had dementia. The greatest increases in risk occurred early in therapy and with relatively high dosages.

The mortality risk associated with short-term antipsychotic treatment in medically ill elderly patients is unknown. Untreated delirium may impose a greater risk of morbidity and mortality than the risk associated with antipsychotics, however. Until more evidence becomes available, we recommend that you try to use low antipsychotic doses, especially for the elderly.

EPS are more common with conventional antipsychotics but also can be associated with the atypicals—particularly with risperidone at doses higher than 4 to 6 mg/d. To minimize EPS risk, monitor delirium patients daily during antipsychotic treatment and identify populations at risk.

QT interval prolongation. A prolonged QT interval increases the risk of ventricular arrhythmias—such as torsades de pointes and ventricular fibrillation—that can lead to syncope, cardiac arrest, or sudden cardiac death. Among the atypicals, ziprasidone has been associated with the highest rates of QT interval prolongation, followed by quetiapine, risperidone, and olanzapine.²⁴ Thioridazine carries the greatest risk among the typical agents.²⁵

When using antipsychotics for delirium, identify patients at risk for QT interval changes and monitor all patients during treatment. Risk factors include older age, female sex, preexisting heart disease, bradycardia, electrolyte abnormalities, and use of drugs that block potassium. APA guidelines recommend discontinuing antipsychotic therapy if QTc exceeds 450 msec or increases >25% from baseline.¹ Consult with a cardiologist when antipsychotic treatment is necessary despite QT prolongation.

Metabolic syndrome. Long-term use of atypical antipsychotics—particularly olanzapine—has been associated with metabolic dysregulation and increased risk of obesity and diabetes. In the absence of data on the atypicals’ short-term effects on metabolism, we recommend careful monitoring for metabolic syndrome when using these agents, especially in patients with preexisting metabolic disturbances.²⁶

Table 4

Monitoring for antipsychotic side effects during delirium treatment

Discontinuing antipsychotics

No evidence-based or expert consensus guidelines have addressed when or how to discontinue antipsychotic treatment of delirium. Several studies—including a randomized, controlled trial by our group¹²—used protocols that reflect expert clinician practice.

Antipsychotic therapy is initiated to control delirium’s symptoms and is presumed to be needed until the causes have been identified or have resolved. Thus, antipsychotics are typically given in 3 phases:

Maintenance. Continue the antipsychotic 7 to 10 days—typically at two-thirds to one-half the initial-phase dosage—to allow delirium causes to be identified and resolve.

Tapering/discontinuation. If delirium symptoms resolve, taper and discontinue the antipsychotic relatively slowly over 3 to 5 days to allow for rapid control should delirium symptoms reemerge. Re-emergence suggests that new or unrecognized causes of delirium are present or identified causes have not resolved.

Related Resources

• American Psychiatric Association. Treating delirium: a quick reference guide. www.psych.org/psych_pract/treatg/quick_ref_guide/DeliriumQRG_4-15-05.pdf.
  
• American Psychiatric Association. Guideline watch: practice guideline for the treatment of patients with delirium. www.psych.org/psych_pract/treatg/pg/Delirium.watch.pdf.
  
• American Psychosocial Oncology Society. Multidisciplinary training in psycho-oncology: delirium. www.apos-society.org/professionals/meetings-ed/webcasts/webcasts-multidisciplinary.aspx.
  

• Aripiprazole • Abilify
  
• Chlorpromazine • various
  
• Haloperidol • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Breitbart is a consultant to Cephalon and a speaker for Cephalon, Janssen Pharmaceutica, Purdue Pharma, Eli Lilly and Company, and Bristol-Myers Squibb.

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

Delirium is a medical emergency that needs to be identified and treated vigorously. Antipsychotics—including haloperidol and atypical agents—effectively manage a wide spectrum of delirium symptoms and are an essential component in the standard multimodal approach.¹ Even so, antipsychotics are not FDA-approved for treating delirium, and evidence on their safety in medically ill patients is limited—particularly in the elderly, in whom delirium occurs most often.

The FDA has warned of increased risk of death when atypical antipsychotics are used to treat behavioral disturbances in elderly patients with dementia.² Similarly, a retrospective study of elderly patients taking antipsychotics found higher mortality rates associated with typical antipsychotics than with atypicals.³

This article discusses the risks and benefits of using antipsychotics to manage delirium. Based on the literature and clinical experience, we offer recommendations on choosing among the available agents and avoiding side effects.

A challenging diagnosis

Delirium is a neuropsychiatric syndrome precipitated by an underlying medical condition or a medication effect on the brain. Its characteristic symptoms—abrupt onset of disturbed consciousness, attention, cognition, and perception—tend to fluctuate during the day. Delirium most often occurs in elderly patients (Box)^1,4-7—particularly with dementia—but also occurs in younger patients with serious illnesses such as cancer or HIV-AIDS.

Delirium is underdiagnosed and under-treated in medical settings,^4,8 most likely because of its protean symptoms (Table 1)⁹ and fluctuating clinical findings. Neurologic abnormalities—including cortical and motor symptoms—also can occur.¹

Mortality risk. Delirium is an independent risk factor for mortality.^1,4,5 It is a marker for serious and potentially life-threatening medical problems, such as organ failure or sepsis. When antipsychotics fail to control delirium, the 3 most common reasons are:

• delirium’s etiology has not been discovered or addressed
  
• delirium’s etiology is resistant to treatment or potentially irreversible
  
• antipsychotic dosage was inadequate.
  

3 subtypes. Delirium is classified as hyperactive, hypoactive, or mixed, depending on arousal disturbance and psychomotor behavior:

• the hyperactive subtype includes hallucinations, delusions, agitation, and disorientation.
  
• the hypoactive subtype includes confusion, sedation, and decreased alertness but rarely hallucinations or delusions.¹
  

Box

Antipsychotics: Limited evidence

• identifying and eliminating contributing factors
  
• instituting nonpharmacologic interventions based on environmental strategies (Table 2)⁴
  
• providing pharmacologic interventions—primarily antipsychotics—as needed.
  

• delirium severity improved with haloperidol, chlorpromazine, olanzapine, risperidone, or quetiapine
  
• comparison trials did not identify any antipsychotic as more efficacious than another.
  

Michaud et al¹¹ reviewed guidelines, systematic reviews, randomized controlled trials, and cohort studies on delirium management. They concluded that the experts agree on 3 points:

• prevention should be emphasized
  
• atypical antipsychotics are not first-choice drugs because of data on adverse events in the elderly
  
• pharmacologic treatment is recommended when the patient’s condition prevents adequate care or puts the patient or staff at risk.
  

Conventional antipsychotics

Haloperidol, the most-studied antipsychotic in delirium treatment, often is the drug of choice because of its high potency, low sedative effect, few anticholinergic side effects, minimal cardiovascular side effects, no active metabolites, and multiple administration routes.¹

Any IV use of injectable haloperidol is off-label, however. If you choose the IV route, monitor patients carefully for cardiac arrhythmias. Haloperidol’s prescribing information carries a new warning of sudden death, QT prolongation, and torsades de pointes in patients given IV haloperidol.

Chlorpromazine. In a double-blind, randomized comparison trial of 30 hospitalized AIDS patients, our group¹² found oral and IM haloperidol (n=11) or chlorpromazine (n=13) highly effective in controlling delirium. Delirium symptoms improved significantly in both hypoactive and hyperactive subtypes with low doses of either antipsychotic (approximately 2 mg of haloperidol equivalent/day).

No patients developed dystonic or dyskinetic symptoms. Lorazepam, given to 6 patients, worsened delirium and cognitive impairment.

Table 1

Recognizing delirium: Diagnostic clinical features*

Nonpharmacologic approaches to managing delirium

Atypicals in delirium: Trial data

Risperidone. Three open-label studies of risperidone in patients with delirium reported minimal risk of sedation and EPS.^13-15

A 7-day, double-blind, flexible-dose trial of 24 patients with delirium¹⁶ found no significant difference between haloperidol (mean 1.71 mg/d) and risperidone (mean 1.02 mg/d) in clinical efficacy or response rate. The authors acknowledged, that they were unable to obtain identical-looking haloperidol and risperidone tablets for the trial.

Kim et al¹⁷ studied dopamine transporter gene polymorphism and use of haloperidol vs risperidone in 42 patients with delirium. Relatively low doses of both antipsychotics showed similar efficacy, and the authors concluded that dopamine transporter gene polymorphism did not influence delirium treatment.

Olanzapine. In an open trial of 79 inpatients with advanced cancer, olanzapine (mean 6.3 mg/d, range 2.5 to 20 mg/d) resolved delirium in 76% of patients, with no incidence of EPS.¹⁸ Age >70, history of dementia, hypoxia, cerebral metastasis, and hypoactive delirium were associated with poor response to olanzapine. This study is unique in assessing olanzapine’s efficacy in different delirium subtypes.

A prospective, randomized trial compared olanzapine (mean 4.5 mg/d, range 2.5 to 13.5 mg/d) with haloperidol (mean 6.5 mg/d, range 1 to 28 mg/d) in patients admitted with delirium to a critical care setting.¹⁹ Both treatment groups showed similar improvement over 5 days. No side effects were reported in the patients receiving olanzapine.

Ziprasidone. In the first case report in which ziprasidone was used to treat delirium,²¹ an HIV/AIDS patient was given 100 mg/d. Delirium symptoms improved, but treatment was discontinued because of side effects (hypokalemia, hypomagnesemia, premature ventricular contractions, and QT interval prolongation).

Aripiprazole. Straker et al²² reported 14 cases delirium treated with aripiprazole, which showed few side effects. Twelve patients had a ≥50% decrease in Delirium Rating Scale scores, and 13 showed improvement in Clinical Global Impression scale scores.

Clinical options

When choosing an antipsychotic to treat delirium, consider the individual patient’s risks of EPS, sedation, anticholinergic side effects, cardiac arrhythmias, and drug-drug interactions.

Haloperidol. When medication is necessary for delirium, American Psychiatric Association (APA) guidelines consider low-dose haloperidol as first-line treatment (see Related Resources). Recommended dosage is 1 to 2 mg (0.25 to 0.5 mg for the elderly) every 4 hours as needed.

Adding oral or IV lorazepam (0.5 to 1 mg every 1 to 2 hours) to haloperidol may help rapidly sedate the agitated delirious patient and minimize the risk of EPS associated with haloperidol.¹ Avoid benzodiazepine monotherapy unless delirium is related to alcohol or benzodiazepine withdrawal.

Chlorpromazine. We have successfully used oral or IV chlorpromazine (12.5 to 50 mg every 4 to 12 hours) instead of haloperidol plus lorazepam when increased sedation was required, especially:

• in the ICU, where close blood pressure monitoring was feasible
  
• for severe agitation in terminally ill patients to decrease distress for the patient, family and staff.
  

Atypical antipsychotics also may be used to treat delirium, as supported by the literature. Recommended dosing, available routes administration routes, and clinical comments are summarized in Table 3.²³

Table 3

Recommended antipsychotic dosing for delirium*

Managing adverse effects

Reassess patients frequently during a delirium episode to adjust the antipsychotic dose, search for underlying causes, and monitor for side effects (Table 4). In frail elderly patients, start with approximately one-half the recommended initial dose to reduce the side effect risk.

Antipsychotics may not be appropriate in certain populations with delirium, particularly in patients with:

• dementia of Lewy body type or Parkinson’s disease dementia
  
• stroke
  
• history of adverse reactions to antipsychotics.
  

Although the FDA advisory did not apply to typical antipsychotics, Wang et al³—in a retrospective cohort of nearly 23,000 patients age >65—found statistically significant higher mortality rates with typical vs atypical antipsychotics. The increased mortality risk with the typical agents was seen whether or not patients had dementia. The greatest increases in risk occurred early in therapy and with relatively high dosages.

The mortality risk associated with short-term antipsychotic treatment in medically ill elderly patients is unknown. Untreated delirium may impose a greater risk of morbidity and mortality than the risk associated with antipsychotics, however. Until more evidence becomes available, we recommend that you try to use low antipsychotic doses, especially for the elderly.

EPS are more common with conventional antipsychotics but also can be associated with the atypicals—particularly with risperidone at doses higher than 4 to 6 mg/d. To minimize EPS risk, monitor delirium patients daily during antipsychotic treatment and identify populations at risk.

QT interval prolongation. A prolonged QT interval increases the risk of ventricular arrhythmias—such as torsades de pointes and ventricular fibrillation—that can lead to syncope, cardiac arrest, or sudden cardiac death. Among the atypicals, ziprasidone has been associated with the highest rates of QT interval prolongation, followed by quetiapine, risperidone, and olanzapine.²⁴ Thioridazine carries the greatest risk among the typical agents.²⁵

When using antipsychotics for delirium, identify patients at risk for QT interval changes and monitor all patients during treatment. Risk factors include older age, female sex, preexisting heart disease, bradycardia, electrolyte abnormalities, and use of drugs that block potassium. APA guidelines recommend discontinuing antipsychotic therapy if QTc exceeds 450 msec or increases >25% from baseline.¹ Consult with a cardiologist when antipsychotic treatment is necessary despite QT prolongation.

Metabolic syndrome. Long-term use of atypical antipsychotics—particularly olanzapine—has been associated with metabolic dysregulation and increased risk of obesity and diabetes. In the absence of data on the atypicals’ short-term effects on metabolism, we recommend careful monitoring for metabolic syndrome when using these agents, especially in patients with preexisting metabolic disturbances.²⁶

Table 4

Monitoring for antipsychotic side effects during delirium treatment

Discontinuing antipsychotics

No evidence-based or expert consensus guidelines have addressed when or how to discontinue antipsychotic treatment of delirium. Several studies—including a randomized, controlled trial by our group¹²—used protocols that reflect expert clinician practice.

Antipsychotic therapy is initiated to control delirium’s symptoms and is presumed to be needed until the causes have been identified or have resolved. Thus, antipsychotics are typically given in 3 phases:

Maintenance. Continue the antipsychotic 7 to 10 days—typically at two-thirds to one-half the initial-phase dosage—to allow delirium causes to be identified and resolve.

Tapering/discontinuation. If delirium symptoms resolve, taper and discontinue the antipsychotic relatively slowly over 3 to 5 days to allow for rapid control should delirium symptoms reemerge. Re-emergence suggests that new or unrecognized causes of delirium are present or identified causes have not resolved.

Related Resources

• American Psychiatric Association. Treating delirium: a quick reference guide. www.psych.org/psych_pract/treatg/quick_ref_guide/DeliriumQRG_4-15-05.pdf.
  
• American Psychiatric Association. Guideline watch: practice guideline for the treatment of patients with delirium. www.psych.org/psych_pract/treatg/pg/Delirium.watch.pdf.
  
• American Psychosocial Oncology Society. Multidisciplinary training in psycho-oncology: delirium. www.apos-society.org/professionals/meetings-ed/webcasts/webcasts-multidisciplinary.aspx.
  

• Aripiprazole • Abilify
  
• Chlorpromazine • various
  
• Haloperidol • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Breitbart is a consultant to Cephalon and a speaker for Cephalon, Janssen Pharmaceutica, Purdue Pharma, Eli Lilly and Company, and Bristol-Myers Squibb.

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

Delirium is a medical emergency that needs to be identified and treated vigorously. Antipsychotics—including haloperidol and atypical agents—effectively manage a wide spectrum of delirium symptoms and are an essential component in the standard multimodal approach.¹ Even so, antipsychotics are not FDA-approved for treating delirium, and evidence on their safety in medically ill patients is limited—particularly in the elderly, in whom delirium occurs most often.

The FDA has warned of increased risk of death when atypical antipsychotics are used to treat behavioral disturbances in elderly patients with dementia.² Similarly, a retrospective study of elderly patients taking antipsychotics found higher mortality rates associated with typical antipsychotics than with atypicals.³

This article discusses the risks and benefits of using antipsychotics to manage delirium. Based on the literature and clinical experience, we offer recommendations on choosing among the available agents and avoiding side effects.

A challenging diagnosis

Delirium is a neuropsychiatric syndrome precipitated by an underlying medical condition or a medication effect on the brain. Its characteristic symptoms—abrupt onset of disturbed consciousness, attention, cognition, and perception—tend to fluctuate during the day. Delirium most often occurs in elderly patients (Box)^1,4-7—particularly with dementia—but also occurs in younger patients with serious illnesses such as cancer or HIV-AIDS.

Delirium is underdiagnosed and under-treated in medical settings,^4,8 most likely because of its protean symptoms (Table 1)⁹ and fluctuating clinical findings. Neurologic abnormalities—including cortical and motor symptoms—also can occur.¹

Mortality risk. Delirium is an independent risk factor for mortality.^1,4,5 It is a marker for serious and potentially life-threatening medical problems, such as organ failure or sepsis. When antipsychotics fail to control delirium, the 3 most common reasons are:

• delirium’s etiology has not been discovered or addressed
  
• delirium’s etiology is resistant to treatment or potentially irreversible
  
• antipsychotic dosage was inadequate.
  

3 subtypes. Delirium is classified as hyperactive, hypoactive, or mixed, depending on arousal disturbance and psychomotor behavior:

• the hyperactive subtype includes hallucinations, delusions, agitation, and disorientation.
  
• the hypoactive subtype includes confusion, sedation, and decreased alertness but rarely hallucinations or delusions.¹
  

Box

Antipsychotics: Limited evidence

• identifying and eliminating contributing factors
  
• instituting nonpharmacologic interventions based on environmental strategies (Table 2)⁴
  
• providing pharmacologic interventions—primarily antipsychotics—as needed.
  

• delirium severity improved with haloperidol, chlorpromazine, olanzapine, risperidone, or quetiapine
  
• comparison trials did not identify any antipsychotic as more efficacious than another.
  

Michaud et al¹¹ reviewed guidelines, systematic reviews, randomized controlled trials, and cohort studies on delirium management. They concluded that the experts agree on 3 points:

• prevention should be emphasized
  
• atypical antipsychotics are not first-choice drugs because of data on adverse events in the elderly
  
• pharmacologic treatment is recommended when the patient’s condition prevents adequate care or puts the patient or staff at risk.
  

Conventional antipsychotics

Haloperidol, the most-studied antipsychotic in delirium treatment, often is the drug of choice because of its high potency, low sedative effect, few anticholinergic side effects, minimal cardiovascular side effects, no active metabolites, and multiple administration routes.¹

Any IV use of injectable haloperidol is off-label, however. If you choose the IV route, monitor patients carefully for cardiac arrhythmias. Haloperidol’s prescribing information carries a new warning of sudden death, QT prolongation, and torsades de pointes in patients given IV haloperidol.

Chlorpromazine. In a double-blind, randomized comparison trial of 30 hospitalized AIDS patients, our group¹² found oral and IM haloperidol (n=11) or chlorpromazine (n=13) highly effective in controlling delirium. Delirium symptoms improved significantly in both hypoactive and hyperactive subtypes with low doses of either antipsychotic (approximately 2 mg of haloperidol equivalent/day).

No patients developed dystonic or dyskinetic symptoms. Lorazepam, given to 6 patients, worsened delirium and cognitive impairment.

Table 1

Recognizing delirium: Diagnostic clinical features*

Nonpharmacologic approaches to managing delirium

Atypicals in delirium: Trial data

Risperidone. Three open-label studies of risperidone in patients with delirium reported minimal risk of sedation and EPS.^13-15

A 7-day, double-blind, flexible-dose trial of 24 patients with delirium¹⁶ found no significant difference between haloperidol (mean 1.71 mg/d) and risperidone (mean 1.02 mg/d) in clinical efficacy or response rate. The authors acknowledged, that they were unable to obtain identical-looking haloperidol and risperidone tablets for the trial.

Kim et al¹⁷ studied dopamine transporter gene polymorphism and use of haloperidol vs risperidone in 42 patients with delirium. Relatively low doses of both antipsychotics showed similar efficacy, and the authors concluded that dopamine transporter gene polymorphism did not influence delirium treatment.

Olanzapine. In an open trial of 79 inpatients with advanced cancer, olanzapine (mean 6.3 mg/d, range 2.5 to 20 mg/d) resolved delirium in 76% of patients, with no incidence of EPS.¹⁸ Age >70, history of dementia, hypoxia, cerebral metastasis, and hypoactive delirium were associated with poor response to olanzapine. This study is unique in assessing olanzapine’s efficacy in different delirium subtypes.

A prospective, randomized trial compared olanzapine (mean 4.5 mg/d, range 2.5 to 13.5 mg/d) with haloperidol (mean 6.5 mg/d, range 1 to 28 mg/d) in patients admitted with delirium to a critical care setting.¹⁹ Both treatment groups showed similar improvement over 5 days. No side effects were reported in the patients receiving olanzapine.

Ziprasidone. In the first case report in which ziprasidone was used to treat delirium,²¹ an HIV/AIDS patient was given 100 mg/d. Delirium symptoms improved, but treatment was discontinued because of side effects (hypokalemia, hypomagnesemia, premature ventricular contractions, and QT interval prolongation).

Aripiprazole. Straker et al²² reported 14 cases delirium treated with aripiprazole, which showed few side effects. Twelve patients had a ≥50% decrease in Delirium Rating Scale scores, and 13 showed improvement in Clinical Global Impression scale scores.

Clinical options

When choosing an antipsychotic to treat delirium, consider the individual patient’s risks of EPS, sedation, anticholinergic side effects, cardiac arrhythmias, and drug-drug interactions.

Haloperidol. When medication is necessary for delirium, American Psychiatric Association (APA) guidelines consider low-dose haloperidol as first-line treatment (see Related Resources). Recommended dosage is 1 to 2 mg (0.25 to 0.5 mg for the elderly) every 4 hours as needed.

Adding oral or IV lorazepam (0.5 to 1 mg every 1 to 2 hours) to haloperidol may help rapidly sedate the agitated delirious patient and minimize the risk of EPS associated with haloperidol.¹ Avoid benzodiazepine monotherapy unless delirium is related to alcohol or benzodiazepine withdrawal.

Chlorpromazine. We have successfully used oral or IV chlorpromazine (12.5 to 50 mg every 4 to 12 hours) instead of haloperidol plus lorazepam when increased sedation was required, especially:

• in the ICU, where close blood pressure monitoring was feasible
  
• for severe agitation in terminally ill patients to decrease distress for the patient, family and staff.
  

Atypical antipsychotics also may be used to treat delirium, as supported by the literature. Recommended dosing, available routes administration routes, and clinical comments are summarized in Table 3.²³

Table 3

Recommended antipsychotic dosing for delirium*

Managing adverse effects

Reassess patients frequently during a delirium episode to adjust the antipsychotic dose, search for underlying causes, and monitor for side effects (Table 4). In frail elderly patients, start with approximately one-half the recommended initial dose to reduce the side effect risk.

Antipsychotics may not be appropriate in certain populations with delirium, particularly in patients with:

• dementia of Lewy body type or Parkinson’s disease dementia
  
• stroke
  
• history of adverse reactions to antipsychotics.
  

Although the FDA advisory did not apply to typical antipsychotics, Wang et al³—in a retrospective cohort of nearly 23,000 patients age >65—found statistically significant higher mortality rates with typical vs atypical antipsychotics. The increased mortality risk with the typical agents was seen whether or not patients had dementia. The greatest increases in risk occurred early in therapy and with relatively high dosages.

The mortality risk associated with short-term antipsychotic treatment in medically ill elderly patients is unknown. Untreated delirium may impose a greater risk of morbidity and mortality than the risk associated with antipsychotics, however. Until more evidence becomes available, we recommend that you try to use low antipsychotic doses, especially for the elderly.

EPS are more common with conventional antipsychotics but also can be associated with the atypicals—particularly with risperidone at doses higher than 4 to 6 mg/d. To minimize EPS risk, monitor delirium patients daily during antipsychotic treatment and identify populations at risk.

QT interval prolongation. A prolonged QT interval increases the risk of ventricular arrhythmias—such as torsades de pointes and ventricular fibrillation—that can lead to syncope, cardiac arrest, or sudden cardiac death. Among the atypicals, ziprasidone has been associated with the highest rates of QT interval prolongation, followed by quetiapine, risperidone, and olanzapine.²⁴ Thioridazine carries the greatest risk among the typical agents.²⁵

When using antipsychotics for delirium, identify patients at risk for QT interval changes and monitor all patients during treatment. Risk factors include older age, female sex, preexisting heart disease, bradycardia, electrolyte abnormalities, and use of drugs that block potassium. APA guidelines recommend discontinuing antipsychotic therapy if QTc exceeds 450 msec or increases >25% from baseline.¹ Consult with a cardiologist when antipsychotic treatment is necessary despite QT prolongation.

Metabolic syndrome. Long-term use of atypical antipsychotics—particularly olanzapine—has been associated with metabolic dysregulation and increased risk of obesity and diabetes. In the absence of data on the atypicals’ short-term effects on metabolism, we recommend careful monitoring for metabolic syndrome when using these agents, especially in patients with preexisting metabolic disturbances.²⁶

Table 4

Monitoring for antipsychotic side effects during delirium treatment

Discontinuing antipsychotics

No evidence-based or expert consensus guidelines have addressed when or how to discontinue antipsychotic treatment of delirium. Several studies—including a randomized, controlled trial by our group¹²—used protocols that reflect expert clinician practice.

Antipsychotic therapy is initiated to control delirium’s symptoms and is presumed to be needed until the causes have been identified or have resolved. Thus, antipsychotics are typically given in 3 phases:

Maintenance. Continue the antipsychotic 7 to 10 days—typically at two-thirds to one-half the initial-phase dosage—to allow delirium causes to be identified and resolve.

Tapering/discontinuation. If delirium symptoms resolve, taper and discontinue the antipsychotic relatively slowly over 3 to 5 days to allow for rapid control should delirium symptoms reemerge. Re-emergence suggests that new or unrecognized causes of delirium are present or identified causes have not resolved.

Related Resources

• American Psychiatric Association. Treating delirium: a quick reference guide. www.psych.org/psych_pract/treatg/quick_ref_guide/DeliriumQRG_4-15-05.pdf.
  
• American Psychiatric Association. Guideline watch: practice guideline for the treatment of patients with delirium. www.psych.org/psych_pract/treatg/pg/Delirium.watch.pdf.
  
• American Psychosocial Oncology Society. Multidisciplinary training in psycho-oncology: delirium. www.apos-society.org/professionals/meetings-ed/webcasts/webcasts-multidisciplinary.aspx.
  

• Aripiprazole • Abilify
  
• Chlorpromazine • various
  
• Haloperidol • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Breitbart is a consultant to Cephalon and a speaker for Cephalon, Janssen Pharmaceutica, Purdue Pharma, Eli Lilly and Company, and Bristol-Myers Squibb.

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

A molecule is a molecule is a molecule—until it becomes identified with a purpose. Consider, for example, (-)-trans-4R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperidine. You probably know this molecule as paroxetine—an antidepressant, of course, but it is more than that. If you examine paroxetine’s FDA-approved indications, it also has anti-panic, anti-social anxiety, anti-obsessive-compulsive disorder, anti-posttraumatic stress disorder, and anti-premenstrual dysphoric disorder effects.

“Antidepressants” have achieved fame as antidepressants; one could say these molecules’ search for meaning has been fulfilled. Yet even within psychiatry, their many other uses (Table) can create semantic misunderstandings. Beyond psychiatry, consider the nondepressed patient with neurocardiogenic syncope who wonders why he’s being treated with an antidepressant.

Rather than calling antidepressants “panaceas,” the better choice is to educate patients about the drugs’ wide spectrum of activity. Let’s look broadly across the so-called antidepressants and examine their varied uses in psychiatry and other medical specialties.

Table

FDA-approved psychiatric indications for serotonin uptake inhibitors*

Pain syndromes

Peripheral neuropathy. The only antidepressant with an FDA-approved pain indication is duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). Its approval for diabetic peripheral neuropathic pain (DPNP) was based on two 12-week, randomized, double-blind, placebo-controlled studies using fixed doses of 60 mg once or twice daily.^1,2 Another SNRI—venlafaxine XR, 150 to 225 mg/d, but not 75 mg/d—also was found to be more effective than placebo for this indication in a 6-week, double-blind study (Box 1).³

Using antidepressants to treat pain syndromes is neither new nor restricted to SNRIs, however. In combined double-blind, cross-over studies of patients with DPNP, Max et al⁴ found:

• moderate or greater pain relief in 74% and 61% of subjects, respectively, from the tricyclics amitriptyline, mean 105 mg/d, and desipramine, mean 111 mg/d—with pain reduced by equal amounts in depressed and nondepressed patients
  
• no statistically significant difference in pain relief between the selective serotonin reuptake inhibitor (SSRI) fluoxetine, 40 mg/d, and placebo.
  

• tricyclics: 1 in every 2 to 3 patients
  
• SNRIs: 1 in every 4 to 5 patients
  
• SSRIs: 1 in every 7 patients.
  

The results of this meta-analysis might not accurately reflect bona fide antidepressants, however. Some of the 38 studies (25 of migraine, 12 of tension headache, 1 of both) included treatment with serotonin antagonists—most commonly pizotifen, which is not available in the United States and does not appear to be an antidepressant.

Back pain. Patients with chronic low back pain (average 10 years) seem to benefit from antidepressants, according to a meta-analysis of 9 randomized, controlled trials by Salerno et al.⁸ The effect on pain in the total 504 patients was “small but significant,” and improvement in function was “small but nonsignificant.” Individual sample sizes also were small, however, and only 2 studies excluded depressed patients.

Fibromyalgia, with chronic generalized musculoskeletal pain and tenderness, has been a focus of antidepressant drug therapy. Goldenberg et al⁹ concluded from an ambitious literature review (505 articles) that evidence of efficacy was strong for amitripty-line and modest for SSRIs and SNRIs.

Overall, antidepressants are generally understood to have analgesic effects in the absence of depression. Benefits for patients with pain syndromes are well established for tricyclics (especially amitriptyline) and recently with SNRIs, whereas SSRIs are less effective.

Box 1

Smoking cessation

Bupropion SR is FDA-approved to aid smoking cessation, and this effect is independent of the drug’s antidepressant activity. Bupropion may act as a nicotine receptor antagonist as well as a norepinephrine dopamine reuptake inhibitor.

Other antidepressants have been studied for smoking cessation, with nortriptyline showing benefit in 2 large placebo-controlled trials. Studies with doxepin, fluoxetine, and moclobemide found little or no benefit for this indication.

Cardiovascular uses

Angina. Monoamine oxidase inhibitor (MAOI) antidepressants were used to treat angina pectoris in the late 1950s and early 1960s. This practice stopped after evidence showed that whereas angina pain may have improved with MAOIs, stress-induced ischemia on ECG did not.

Antiarrhythmia. Tricyclics had a brief fling in cardiovascular therapeutics when their quinidine-like class I antiarrhythmic activity was recognized. Imipramine was one of several drugs included in the Cardiac Arrhythmia Pilot Study in the 1980s that involved 502 postmyocardial infarction patients with ventricular arrhythmias. Imipramine was the least effective of the 4 drugs studied and the least well tolerated.¹³

Box 2

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.

A molecule is a molecule is a molecule—until it becomes identified with a purpose. Consider, for example, (-)-trans-4R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperidine. You probably know this molecule as paroxetine—an antidepressant, of course, but it is more than that. If you examine paroxetine’s FDA-approved indications, it also has anti-panic, anti-social anxiety, anti-obsessive-compulsive disorder, anti-posttraumatic stress disorder, and anti-premenstrual dysphoric disorder effects.

“Antidepressants” have achieved fame as antidepressants; one could say these molecules’ search for meaning has been fulfilled. Yet even within psychiatry, their many other uses (Table) can create semantic misunderstandings. Beyond psychiatry, consider the nondepressed patient with neurocardiogenic syncope who wonders why he’s being treated with an antidepressant.

Rather than calling antidepressants “panaceas,” the better choice is to educate patients about the drugs’ wide spectrum of activity. Let’s look broadly across the so-called antidepressants and examine their varied uses in psychiatry and other medical specialties.

Table

FDA-approved psychiatric indications for serotonin uptake inhibitors*

Pain syndromes

Peripheral neuropathy. The only antidepressant with an FDA-approved pain indication is duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). Its approval for diabetic peripheral neuropathic pain (DPNP) was based on two 12-week, randomized, double-blind, placebo-controlled studies using fixed doses of 60 mg once or twice daily.^1,2 Another SNRI—venlafaxine XR, 150 to 225 mg/d, but not 75 mg/d—also was found to be more effective than placebo for this indication in a 6-week, double-blind study (Box 1).³

Using antidepressants to treat pain syndromes is neither new nor restricted to SNRIs, however. In combined double-blind, cross-over studies of patients with DPNP, Max et al⁴ found:

• moderate or greater pain relief in 74% and 61% of subjects, respectively, from the tricyclics amitriptyline, mean 105 mg/d, and desipramine, mean 111 mg/d—with pain reduced by equal amounts in depressed and nondepressed patients
  
• no statistically significant difference in pain relief between the selective serotonin reuptake inhibitor (SSRI) fluoxetine, 40 mg/d, and placebo.
  

• tricyclics: 1 in every 2 to 3 patients
  
• SNRIs: 1 in every 4 to 5 patients
  
• SSRIs: 1 in every 7 patients.
  

The results of this meta-analysis might not accurately reflect bona fide antidepressants, however. Some of the 38 studies (25 of migraine, 12 of tension headache, 1 of both) included treatment with serotonin antagonists—most commonly pizotifen, which is not available in the United States and does not appear to be an antidepressant.

Back pain. Patients with chronic low back pain (average 10 years) seem to benefit from antidepressants, according to a meta-analysis of 9 randomized, controlled trials by Salerno et al.⁸ The effect on pain in the total 504 patients was “small but significant,” and improvement in function was “small but nonsignificant.” Individual sample sizes also were small, however, and only 2 studies excluded depressed patients.

Fibromyalgia, with chronic generalized musculoskeletal pain and tenderness, has been a focus of antidepressant drug therapy. Goldenberg et al⁹ concluded from an ambitious literature review (505 articles) that evidence of efficacy was strong for amitripty-line and modest for SSRIs and SNRIs.

Overall, antidepressants are generally understood to have analgesic effects in the absence of depression. Benefits for patients with pain syndromes are well established for tricyclics (especially amitriptyline) and recently with SNRIs, whereas SSRIs are less effective.

Box 1

Smoking cessation

Bupropion SR is FDA-approved to aid smoking cessation, and this effect is independent of the drug’s antidepressant activity. Bupropion may act as a nicotine receptor antagonist as well as a norepinephrine dopamine reuptake inhibitor.

Other antidepressants have been studied for smoking cessation, with nortriptyline showing benefit in 2 large placebo-controlled trials. Studies with doxepin, fluoxetine, and moclobemide found little or no benefit for this indication.

Cardiovascular uses

Angina. Monoamine oxidase inhibitor (MAOI) antidepressants were used to treat angina pectoris in the late 1950s and early 1960s. This practice stopped after evidence showed that whereas angina pain may have improved with MAOIs, stress-induced ischemia on ECG did not.

Antiarrhythmia. Tricyclics had a brief fling in cardiovascular therapeutics when their quinidine-like class I antiarrhythmic activity was recognized. Imipramine was one of several drugs included in the Cardiac Arrhythmia Pilot Study in the 1980s that involved 502 postmyocardial infarction patients with ventricular arrhythmias. Imipramine was the least effective of the 4 drugs studied and the least well tolerated.¹³

Box 2

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.

A molecule is a molecule is a molecule—until it becomes identified with a purpose. Consider, for example, (-)-trans-4R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperidine. You probably know this molecule as paroxetine—an antidepressant, of course, but it is more than that. If you examine paroxetine’s FDA-approved indications, it also has anti-panic, anti-social anxiety, anti-obsessive-compulsive disorder, anti-posttraumatic stress disorder, and anti-premenstrual dysphoric disorder effects.

“Antidepressants” have achieved fame as antidepressants; one could say these molecules’ search for meaning has been fulfilled. Yet even within psychiatry, their many other uses (Table) can create semantic misunderstandings. Beyond psychiatry, consider the nondepressed patient with neurocardiogenic syncope who wonders why he’s being treated with an antidepressant.

Rather than calling antidepressants “panaceas,” the better choice is to educate patients about the drugs’ wide spectrum of activity. Let’s look broadly across the so-called antidepressants and examine their varied uses in psychiatry and other medical specialties.

Table

FDA-approved psychiatric indications for serotonin uptake inhibitors*

Pain syndromes

Peripheral neuropathy. The only antidepressant with an FDA-approved pain indication is duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). Its approval for diabetic peripheral neuropathic pain (DPNP) was based on two 12-week, randomized, double-blind, placebo-controlled studies using fixed doses of 60 mg once or twice daily.^1,2 Another SNRI—venlafaxine XR, 150 to 225 mg/d, but not 75 mg/d—also was found to be more effective than placebo for this indication in a 6-week, double-blind study (Box 1).³

Using antidepressants to treat pain syndromes is neither new nor restricted to SNRIs, however. In combined double-blind, cross-over studies of patients with DPNP, Max et al⁴ found:

• moderate or greater pain relief in 74% and 61% of subjects, respectively, from the tricyclics amitriptyline, mean 105 mg/d, and desipramine, mean 111 mg/d—with pain reduced by equal amounts in depressed and nondepressed patients
  
• no statistically significant difference in pain relief between the selective serotonin reuptake inhibitor (SSRI) fluoxetine, 40 mg/d, and placebo.
  

• tricyclics: 1 in every 2 to 3 patients
  
• SNRIs: 1 in every 4 to 5 patients
  
• SSRIs: 1 in every 7 patients.
  

The results of this meta-analysis might not accurately reflect bona fide antidepressants, however. Some of the 38 studies (25 of migraine, 12 of tension headache, 1 of both) included treatment with serotonin antagonists—most commonly pizotifen, which is not available in the United States and does not appear to be an antidepressant.

Back pain. Patients with chronic low back pain (average 10 years) seem to benefit from antidepressants, according to a meta-analysis of 9 randomized, controlled trials by Salerno et al.⁸ The effect on pain in the total 504 patients was “small but significant,” and improvement in function was “small but nonsignificant.” Individual sample sizes also were small, however, and only 2 studies excluded depressed patients.

Fibromyalgia, with chronic generalized musculoskeletal pain and tenderness, has been a focus of antidepressant drug therapy. Goldenberg et al⁹ concluded from an ambitious literature review (505 articles) that evidence of efficacy was strong for amitripty-line and modest for SSRIs and SNRIs.

Overall, antidepressants are generally understood to have analgesic effects in the absence of depression. Benefits for patients with pain syndromes are well established for tricyclics (especially amitriptyline) and recently with SNRIs, whereas SSRIs are less effective.

Box 1

Smoking cessation

Bupropion SR is FDA-approved to aid smoking cessation, and this effect is independent of the drug’s antidepressant activity. Bupropion may act as a nicotine receptor antagonist as well as a norepinephrine dopamine reuptake inhibitor.

Other antidepressants have been studied for smoking cessation, with nortriptyline showing benefit in 2 large placebo-controlled trials. Studies with doxepin, fluoxetine, and moclobemide found little or no benefit for this indication.

Cardiovascular uses

Angina. Monoamine oxidase inhibitor (MAOI) antidepressants were used to treat angina pectoris in the late 1950s and early 1960s. This practice stopped after evidence showed that whereas angina pain may have improved with MAOIs, stress-induced ischemia on ECG did not.

Antiarrhythmia. Tricyclics had a brief fling in cardiovascular therapeutics when their quinidine-like class I antiarrhythmic activity was recognized. Imipramine was one of several drugs included in the Cardiac Arrhythmia Pilot Study in the 1980s that involved 502 postmyocardial infarction patients with ventricular arrhythmias. Imipramine was the least effective of the 4 drugs studied and the least well tolerated.¹³

Box 2

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.

When does bipolar disorder begin? That question confounds clinicians, worries parents, and is leading researchers such as Kiki D. Chang, MD, to look for answers in families with this highly heritable disorder.

“Parents with bipolar disorder know what’s happening if their children have early symptoms,” Dr. Chang says. “They tell me, ‘I don’t want my child to go through what I went through, and he’s having the same symptoms I did.’”

Dr. Chang believes early psychotherapy and medication might prevent prodromal bipolar disorder from fully developing. His team at Stanford University is among those seeking genetic and brain imaging biomarkers to make a pediatric bipolar diagnosis more reliable. Lack of age-specific criteria may be causing overdiagnosis, as suggested by a 40-fold increase in 10 years in the number of children and adolescents being treated for bipolar disorder.¹

In this interview by Robert A. Kowatch, MD, PhD, Dr. Chang describes a child with probable early signs of bipolar disorder and discusses why early intervention is both complicated and promising.

Children at risk for bipolarity

DR. KOWATCH: You’re studying children considered at high risk for developing bipolar disorder; why are these studies important?

DR. CHANG: High-risk children represent a chance to understand risk factors for developing bipolar disorder and what the early symptoms are. By “high risk,” we mean children and adolescents who possess a genetic predisposition toward bipolar disorder.

Bipolar disorder develops over time; a boy such as “Brian” (Box 1) likely would have gone 3 to 5 years on the stimulant—not doing well—until he had a manic episode at age 14 or 15. The full mood episode usually does not develop until later, with the right—or you could say wrong— combination of environment and stressors acting on a genetic predisposition.

DR. KOWATCH: Do the parents of the children you’re studying have bipolar disorder?

DR. CHANG: Yes; we’re studying what we call “bipolar offspring”—children with biological parents with bipolar disorder (Box 2).^2-4 One also could look at siblings; having a brother or sister with bipolar disorder increases risk as well. If you search back in these families, usually you’ll find many relatives with bipolar disorder who reflect the child’s genetic predisposition.

Box 1

‘Kindling’ in bipolar disorder

DR. KOWATCH: What have you seen in children whose parents have bipolar disorder?

DR. CHANG: We’ve tracked more than 200 bipolar offspring for up to 10 years. In some families we’ve seen the natural progression toward full mania and bipolar disorder.

We’ve also seen children who start to show symptoms but don’t develop full bipolar disorder. These children have had clinical treatment, so we’re not sure if the intervention prevented full bipolar disorder or if they would not have developed it anyway. Some children have developed mood symptoms and other psychiatric problems that have resolved with early intervention.

DR. CHANG: Kindling, which originally referred to seizure disorders, also has been applied to affective disorders.⁵ Early stressors and triggers appear to add up over time and combine with genetic predisposition to create a full mood episode. After that break, it becomes easier and easier to have the next episode, and the disorder becomes chronic and more difficult to treat.

The goal of our work is to stop kindling in bipolar disorder—to prevent environmental or developmental “sparks” from interacting with genetic predisposition and igniting a chronic, spontaneous course of mood episodes.

Brain imaging biomarkers

DR. KOWATCH: Are researchers finding biomarkers for bipolar disorder?

DR. CHANG: The field is young but light-years ahead of where we were 10 years ago. Brain imaging has revealed consistently abnormal areas in children with bipolar disorder. These abnormalities are seen in adults with bipolar disorder as well, but chronic illness, substance abuse, and medication exposure affect the findings in adults. Children have had less exposure to these confounding variables.

We and other groups have identified areas of the prefrontal cortex, amygdala, cerebellum, and striatum that could represent biomarkers, although I wouldn’t say yet that there are any markers per se. A decrease in amygdala volume has been found consistently in children with bipolar disorder, for example, but it’s not specific to bipolar disorder. So we have a way to go before we find specific biomarkers.

In the future, clinicians will probably use a set of 10 to 20 biomarkers, and the more biomarkers a patient has, the greater the risk for bipolar disorder. Once a battery of biomarkers has been put together, the more certain a bipolar disorder diagnosis will become.

Genetic biomarkers

DR. KOWATCH: We’ve talked about high-risk families; are there genetic markers for bipolar disorder?

If you look at common polymorphisms in a set of genes, eventually you’ll be able to calculate the risk that a person will develop bipolar disorder. We’re also investigating whether genes control the age of onset.

DR. KOWATCH: How are you looking for genetic markers in the high-risk children you’re studying?

DR. CHANG: We start with the proband—the child of a bipolar parent—and then study as much of the family as we can. Approximately 50% of the probands’ first- or second-degree relatives have a mood disorder—so our samples are highly loaded.

We’re interested in the interaction between genes and brain function and structure: How do genetic predispositions lead to brain differences that create vulnerability for mood disorders—in this case, bipolar disorder?

To explore that question, we’re starting a 5-year study funded by the National Institutes of Health (NIH). We’re recruiting 50 sibling pairs in which 1 child has early bipolar symptoms and the other is healthy. We will compare these pairs’ genetic and brain imaging profiles with those of 30 healthy children with no genetic risk for bipolar disorder, as far as we can tell.

Something makes 1 child develop bipolar disorder and another child not. By matching siblings with shared environments, we’re trying to eliminate environmental factors and look at their genetic and brain function differences. We’ll use functional brain imaging to look at how children respond to mood-related tasks and standard tasks involving facial emotion exposure to activate brain areas bipolar disorder is thought to affect.

Preventing bipolar ‘kindling’

DR. KOWATCH: What interventions might interrupt kindling and help prevent bipolar I disorder from developing in high risk children?

DR. CHANG: Families affected by bipolar disorder are characterized by stress and high expressed emotion; they tend to fight a lot, and we’re trying to improve communication and their ability to work together. We think reduced stress could halt the progression of the disorder in at-risk children.

Our group is collaborating with Dr. David Miklowitz at the University of Colorado to develop a family psychotherapy program for children who have at least 1 parent or sibling with bipolar disorder and are showing early bipolar symptoms. In a 3-year, NIH-funded treatment development study, 40 children will be randomly assigned to receive 12 sessions of weekly family-focused therapy (FFT) or treatment as usual.

We also think some medications have potential for protecting the brain against the progression of bipolar disorder. In vitro evidence exists for lithium, valproate, and carbamazepine to some extent, other anticonvulsants such as lamotrigine, and atypical antipsychotics such as quetiapine and olanzapine. A few preliminary clinical trials have been conducted (Box 3)^9-11 but no longitudinal studies.

Box 3

RECOMMENDATIONS

DR. KOWATCH: What do you recommend that psychiatrists do to help children at risk for bipolar disorder?

DR. CHANG: Ask your adult patients with bipolar disorder how their children are doing. If a child is not doing well, consider referral to a child and adolescent psychiatrist or take an interest yourself and assess the child for early signs of bipolar disorder.

DR. KOWATCH: What are the prodromal symptoms in children and adolescents?

DR. CHANG: In the past, the earliest reported symptoms were thought to include extreme hyperactivity, inappropriate sexuality, and severe depression at a very young age (preschool or school age children). Now data point to 2 major pathways toward bipolar disorder:

• early-onset depression, which elevates risk for later mania
  
• early attention-deficit/hyperactivity disorder (ADHD).
  

DR. KOWATCH: So you’ve got a group with depression and a group with severe ADHD that might develop into bipolar disorder?

DR. CHANG: The ADHD need not be severe. In these children, ADHD may reflect an underlying brain development trajectory toward mood dysregulation. We’ve also seen anxiety as an initial condition. A cross-sectional study found anxiety to be prevalent in bipolar offspring and a possible risk factor for later mania.¹²

Anxiety is very common in children, so it’s hard to tell if it’s a precursor for bipolar disorder in an individual child. But looking back, a lot of children who develop bipolar disorder had early anxiety, which may be a marker that they were not coping well with stress. What starts leaking out as anxiety eventually may leak out as a full mood episode.

DR. CHANG: Yes, although sometimes the risk comes not from the parents but from a second-degree or more distant relative. We have seen plenty of families in which (as far as we can tell) the parents don’t have any mood disorders, but a child has full bipolar disorder that began over time—as it usually does in bipolar offspring.

Children or adolescents who have first-break episodes after very little pre-morbid dysfunction comprise yet another subset. This group tends to present with episodic manic depression.

DR. KOWATCH: Do you think children with bipolar disorder have clear mood episodes?

DR. CHANG: Our research is trying to bypass that debate. We’re trying to understand whether biomarkers in the brain or blood can be used to distinguish different types of bipolar disorders, rather than relying on symptomatology.

Related resources

• Chang KD, Howe M, Gallelli, K, Miklowitz D. Prevention of pediatric bipolar disorder: integration of neurobiological and psychosocial processes. Ann NY Acad Sci 2006;1094:235–47.
  
• Chang KD, Gallelli KA. Bipolar disorders and genetics: clinical implications of high heritability. Medscape Psychiatry & Mental Health 2004;9(2). Available at: http://www.medscape.com/viewarticle/489331.
  
• Miklowitz D, Biuckians A, Richards JA. Early-onset bipolar disorder: a family treatment perspective. Dev Psychopathol 2006;18(4):1247–65.
  

• Carbamazepine • various
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakene, Depakote
  

Dr. Chang receives research support from AstraZeneca, Eli Lilly and Company, Otsuka, and the National Institute of Mental Health. He is a consultant to Abbott Laboratories, GlaxoSmithKline, and Shire, and a speaker for Abbott Laboratories and AstraZeneca.

Dr. Kowatch receives research support from Bristol-Myers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a speaker for Abbott Laboratories and AstraZeneca.

When does bipolar disorder begin? That question confounds clinicians, worries parents, and is leading researchers such as Kiki D. Chang, MD, to look for answers in families with this highly heritable disorder.

“Parents with bipolar disorder know what’s happening if their children have early symptoms,” Dr. Chang says. “They tell me, ‘I don’t want my child to go through what I went through, and he’s having the same symptoms I did.’”

Dr. Chang believes early psychotherapy and medication might prevent prodromal bipolar disorder from fully developing. His team at Stanford University is among those seeking genetic and brain imaging biomarkers to make a pediatric bipolar diagnosis more reliable. Lack of age-specific criteria may be causing overdiagnosis, as suggested by a 40-fold increase in 10 years in the number of children and adolescents being treated for bipolar disorder.¹

In this interview by Robert A. Kowatch, MD, PhD, Dr. Chang describes a child with probable early signs of bipolar disorder and discusses why early intervention is both complicated and promising.

Children at risk for bipolarity

DR. KOWATCH: You’re studying children considered at high risk for developing bipolar disorder; why are these studies important?

DR. CHANG: High-risk children represent a chance to understand risk factors for developing bipolar disorder and what the early symptoms are. By “high risk,” we mean children and adolescents who possess a genetic predisposition toward bipolar disorder.

Bipolar disorder develops over time; a boy such as “Brian” (Box 1) likely would have gone 3 to 5 years on the stimulant—not doing well—until he had a manic episode at age 14 or 15. The full mood episode usually does not develop until later, with the right—or you could say wrong— combination of environment and stressors acting on a genetic predisposition.

DR. KOWATCH: Do the parents of the children you’re studying have bipolar disorder?

DR. CHANG: Yes; we’re studying what we call “bipolar offspring”—children with biological parents with bipolar disorder (Box 2).^2-4 One also could look at siblings; having a brother or sister with bipolar disorder increases risk as well. If you search back in these families, usually you’ll find many relatives with bipolar disorder who reflect the child’s genetic predisposition.

Box 1

‘Kindling’ in bipolar disorder

DR. KOWATCH: What have you seen in children whose parents have bipolar disorder?

DR. CHANG: We’ve tracked more than 200 bipolar offspring for up to 10 years. In some families we’ve seen the natural progression toward full mania and bipolar disorder.

We’ve also seen children who start to show symptoms but don’t develop full bipolar disorder. These children have had clinical treatment, so we’re not sure if the intervention prevented full bipolar disorder or if they would not have developed it anyway. Some children have developed mood symptoms and other psychiatric problems that have resolved with early intervention.

DR. CHANG: Kindling, which originally referred to seizure disorders, also has been applied to affective disorders.⁵ Early stressors and triggers appear to add up over time and combine with genetic predisposition to create a full mood episode. After that break, it becomes easier and easier to have the next episode, and the disorder becomes chronic and more difficult to treat.

The goal of our work is to stop kindling in bipolar disorder—to prevent environmental or developmental “sparks” from interacting with genetic predisposition and igniting a chronic, spontaneous course of mood episodes.

Brain imaging biomarkers

DR. KOWATCH: Are researchers finding biomarkers for bipolar disorder?

DR. CHANG: The field is young but light-years ahead of where we were 10 years ago. Brain imaging has revealed consistently abnormal areas in children with bipolar disorder. These abnormalities are seen in adults with bipolar disorder as well, but chronic illness, substance abuse, and medication exposure affect the findings in adults. Children have had less exposure to these confounding variables.

We and other groups have identified areas of the prefrontal cortex, amygdala, cerebellum, and striatum that could represent biomarkers, although I wouldn’t say yet that there are any markers per se. A decrease in amygdala volume has been found consistently in children with bipolar disorder, for example, but it’s not specific to bipolar disorder. So we have a way to go before we find specific biomarkers.

In the future, clinicians will probably use a set of 10 to 20 biomarkers, and the more biomarkers a patient has, the greater the risk for bipolar disorder. Once a battery of biomarkers has been put together, the more certain a bipolar disorder diagnosis will become.

Genetic biomarkers

DR. KOWATCH: We’ve talked about high-risk families; are there genetic markers for bipolar disorder?

If you look at common polymorphisms in a set of genes, eventually you’ll be able to calculate the risk that a person will develop bipolar disorder. We’re also investigating whether genes control the age of onset.

DR. KOWATCH: How are you looking for genetic markers in the high-risk children you’re studying?

DR. CHANG: We start with the proband—the child of a bipolar parent—and then study as much of the family as we can. Approximately 50% of the probands’ first- or second-degree relatives have a mood disorder—so our samples are highly loaded.

We’re interested in the interaction between genes and brain function and structure: How do genetic predispositions lead to brain differences that create vulnerability for mood disorders—in this case, bipolar disorder?

To explore that question, we’re starting a 5-year study funded by the National Institutes of Health (NIH). We’re recruiting 50 sibling pairs in which 1 child has early bipolar symptoms and the other is healthy. We will compare these pairs’ genetic and brain imaging profiles with those of 30 healthy children with no genetic risk for bipolar disorder, as far as we can tell.

Something makes 1 child develop bipolar disorder and another child not. By matching siblings with shared environments, we’re trying to eliminate environmental factors and look at their genetic and brain function differences. We’ll use functional brain imaging to look at how children respond to mood-related tasks and standard tasks involving facial emotion exposure to activate brain areas bipolar disorder is thought to affect.

Preventing bipolar ‘kindling’

DR. KOWATCH: What interventions might interrupt kindling and help prevent bipolar I disorder from developing in high risk children?

DR. CHANG: Families affected by bipolar disorder are characterized by stress and high expressed emotion; they tend to fight a lot, and we’re trying to improve communication and their ability to work together. We think reduced stress could halt the progression of the disorder in at-risk children.

Our group is collaborating with Dr. David Miklowitz at the University of Colorado to develop a family psychotherapy program for children who have at least 1 parent or sibling with bipolar disorder and are showing early bipolar symptoms. In a 3-year, NIH-funded treatment development study, 40 children will be randomly assigned to receive 12 sessions of weekly family-focused therapy (FFT) or treatment as usual.

We also think some medications have potential for protecting the brain against the progression of bipolar disorder. In vitro evidence exists for lithium, valproate, and carbamazepine to some extent, other anticonvulsants such as lamotrigine, and atypical antipsychotics such as quetiapine and olanzapine. A few preliminary clinical trials have been conducted (Box 3)^9-11 but no longitudinal studies.

Box 3

RECOMMENDATIONS

DR. KOWATCH: What do you recommend that psychiatrists do to help children at risk for bipolar disorder?

DR. CHANG: Ask your adult patients with bipolar disorder how their children are doing. If a child is not doing well, consider referral to a child and adolescent psychiatrist or take an interest yourself and assess the child for early signs of bipolar disorder.

DR. KOWATCH: What are the prodromal symptoms in children and adolescents?

DR. CHANG: In the past, the earliest reported symptoms were thought to include extreme hyperactivity, inappropriate sexuality, and severe depression at a very young age (preschool or school age children). Now data point to 2 major pathways toward bipolar disorder:

• early-onset depression, which elevates risk for later mania
  
• early attention-deficit/hyperactivity disorder (ADHD).
  

DR. KOWATCH: So you’ve got a group with depression and a group with severe ADHD that might develop into bipolar disorder?

DR. CHANG: The ADHD need not be severe. In these children, ADHD may reflect an underlying brain development trajectory toward mood dysregulation. We’ve also seen anxiety as an initial condition. A cross-sectional study found anxiety to be prevalent in bipolar offspring and a possible risk factor for later mania.¹²

Anxiety is very common in children, so it’s hard to tell if it’s a precursor for bipolar disorder in an individual child. But looking back, a lot of children who develop bipolar disorder had early anxiety, which may be a marker that they were not coping well with stress. What starts leaking out as anxiety eventually may leak out as a full mood episode.

DR. CHANG: Yes, although sometimes the risk comes not from the parents but from a second-degree or more distant relative. We have seen plenty of families in which (as far as we can tell) the parents don’t have any mood disorders, but a child has full bipolar disorder that began over time—as it usually does in bipolar offspring.

Children or adolescents who have first-break episodes after very little pre-morbid dysfunction comprise yet another subset. This group tends to present with episodic manic depression.

DR. KOWATCH: Do you think children with bipolar disorder have clear mood episodes?

DR. CHANG: Our research is trying to bypass that debate. We’re trying to understand whether biomarkers in the brain or blood can be used to distinguish different types of bipolar disorders, rather than relying on symptomatology.

Related resources

• Chang KD, Howe M, Gallelli, K, Miklowitz D. Prevention of pediatric bipolar disorder: integration of neurobiological and psychosocial processes. Ann NY Acad Sci 2006;1094:235–47.
  
• Chang KD, Gallelli KA. Bipolar disorders and genetics: clinical implications of high heritability. Medscape Psychiatry & Mental Health 2004;9(2). Available at: http://www.medscape.com/viewarticle/489331.
  
• Miklowitz D, Biuckians A, Richards JA. Early-onset bipolar disorder: a family treatment perspective. Dev Psychopathol 2006;18(4):1247–65.
  

• Carbamazepine • various
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakene, Depakote
  

Dr. Chang receives research support from AstraZeneca, Eli Lilly and Company, Otsuka, and the National Institute of Mental Health. He is a consultant to Abbott Laboratories, GlaxoSmithKline, and Shire, and a speaker for Abbott Laboratories and AstraZeneca.

Dr. Kowatch receives research support from Bristol-Myers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a speaker for Abbott Laboratories and AstraZeneca.

When does bipolar disorder begin? That question confounds clinicians, worries parents, and is leading researchers such as Kiki D. Chang, MD, to look for answers in families with this highly heritable disorder.

“Parents with bipolar disorder know what’s happening if their children have early symptoms,” Dr. Chang says. “They tell me, ‘I don’t want my child to go through what I went through, and he’s having the same symptoms I did.’”

Dr. Chang believes early psychotherapy and medication might prevent prodromal bipolar disorder from fully developing. His team at Stanford University is among those seeking genetic and brain imaging biomarkers to make a pediatric bipolar diagnosis more reliable. Lack of age-specific criteria may be causing overdiagnosis, as suggested by a 40-fold increase in 10 years in the number of children and adolescents being treated for bipolar disorder.¹

In this interview by Robert A. Kowatch, MD, PhD, Dr. Chang describes a child with probable early signs of bipolar disorder and discusses why early intervention is both complicated and promising.

Children at risk for bipolarity

DR. KOWATCH: You’re studying children considered at high risk for developing bipolar disorder; why are these studies important?

DR. CHANG: High-risk children represent a chance to understand risk factors for developing bipolar disorder and what the early symptoms are. By “high risk,” we mean children and adolescents who possess a genetic predisposition toward bipolar disorder.

Bipolar disorder develops over time; a boy such as “Brian” (Box 1) likely would have gone 3 to 5 years on the stimulant—not doing well—until he had a manic episode at age 14 or 15. The full mood episode usually does not develop until later, with the right—or you could say wrong— combination of environment and stressors acting on a genetic predisposition.

DR. KOWATCH: Do the parents of the children you’re studying have bipolar disorder?

DR. CHANG: Yes; we’re studying what we call “bipolar offspring”—children with biological parents with bipolar disorder (Box 2).^2-4 One also could look at siblings; having a brother or sister with bipolar disorder increases risk as well. If you search back in these families, usually you’ll find many relatives with bipolar disorder who reflect the child’s genetic predisposition.

Box 1

‘Kindling’ in bipolar disorder

DR. KOWATCH: What have you seen in children whose parents have bipolar disorder?

DR. CHANG: We’ve tracked more than 200 bipolar offspring for up to 10 years. In some families we’ve seen the natural progression toward full mania and bipolar disorder.

We’ve also seen children who start to show symptoms but don’t develop full bipolar disorder. These children have had clinical treatment, so we’re not sure if the intervention prevented full bipolar disorder or if they would not have developed it anyway. Some children have developed mood symptoms and other psychiatric problems that have resolved with early intervention.

DR. CHANG: Kindling, which originally referred to seizure disorders, also has been applied to affective disorders.⁵ Early stressors and triggers appear to add up over time and combine with genetic predisposition to create a full mood episode. After that break, it becomes easier and easier to have the next episode, and the disorder becomes chronic and more difficult to treat.

The goal of our work is to stop kindling in bipolar disorder—to prevent environmental or developmental “sparks” from interacting with genetic predisposition and igniting a chronic, spontaneous course of mood episodes.

Brain imaging biomarkers

DR. KOWATCH: Are researchers finding biomarkers for bipolar disorder?

DR. CHANG: The field is young but light-years ahead of where we were 10 years ago. Brain imaging has revealed consistently abnormal areas in children with bipolar disorder. These abnormalities are seen in adults with bipolar disorder as well, but chronic illness, substance abuse, and medication exposure affect the findings in adults. Children have had less exposure to these confounding variables.

We and other groups have identified areas of the prefrontal cortex, amygdala, cerebellum, and striatum that could represent biomarkers, although I wouldn’t say yet that there are any markers per se. A decrease in amygdala volume has been found consistently in children with bipolar disorder, for example, but it’s not specific to bipolar disorder. So we have a way to go before we find specific biomarkers.

In the future, clinicians will probably use a set of 10 to 20 biomarkers, and the more biomarkers a patient has, the greater the risk for bipolar disorder. Once a battery of biomarkers has been put together, the more certain a bipolar disorder diagnosis will become.

Genetic biomarkers

DR. KOWATCH: We’ve talked about high-risk families; are there genetic markers for bipolar disorder?

If you look at common polymorphisms in a set of genes, eventually you’ll be able to calculate the risk that a person will develop bipolar disorder. We’re also investigating whether genes control the age of onset.

DR. KOWATCH: How are you looking for genetic markers in the high-risk children you’re studying?

DR. CHANG: We start with the proband—the child of a bipolar parent—and then study as much of the family as we can. Approximately 50% of the probands’ first- or second-degree relatives have a mood disorder—so our samples are highly loaded.

We’re interested in the interaction between genes and brain function and structure: How do genetic predispositions lead to brain differences that create vulnerability for mood disorders—in this case, bipolar disorder?

To explore that question, we’re starting a 5-year study funded by the National Institutes of Health (NIH). We’re recruiting 50 sibling pairs in which 1 child has early bipolar symptoms and the other is healthy. We will compare these pairs’ genetic and brain imaging profiles with those of 30 healthy children with no genetic risk for bipolar disorder, as far as we can tell.

Something makes 1 child develop bipolar disorder and another child not. By matching siblings with shared environments, we’re trying to eliminate environmental factors and look at their genetic and brain function differences. We’ll use functional brain imaging to look at how children respond to mood-related tasks and standard tasks involving facial emotion exposure to activate brain areas bipolar disorder is thought to affect.

Preventing bipolar ‘kindling’

DR. KOWATCH: What interventions might interrupt kindling and help prevent bipolar I disorder from developing in high risk children?

DR. CHANG: Families affected by bipolar disorder are characterized by stress and high expressed emotion; they tend to fight a lot, and we’re trying to improve communication and their ability to work together. We think reduced stress could halt the progression of the disorder in at-risk children.

Our group is collaborating with Dr. David Miklowitz at the University of Colorado to develop a family psychotherapy program for children who have at least 1 parent or sibling with bipolar disorder and are showing early bipolar symptoms. In a 3-year, NIH-funded treatment development study, 40 children will be randomly assigned to receive 12 sessions of weekly family-focused therapy (FFT) or treatment as usual.

We also think some medications have potential for protecting the brain against the progression of bipolar disorder. In vitro evidence exists for lithium, valproate, and carbamazepine to some extent, other anticonvulsants such as lamotrigine, and atypical antipsychotics such as quetiapine and olanzapine. A few preliminary clinical trials have been conducted (Box 3)^9-11 but no longitudinal studies.

Box 3

RECOMMENDATIONS

DR. KOWATCH: What do you recommend that psychiatrists do to help children at risk for bipolar disorder?

DR. CHANG: Ask your adult patients with bipolar disorder how their children are doing. If a child is not doing well, consider referral to a child and adolescent psychiatrist or take an interest yourself and assess the child for early signs of bipolar disorder.

DR. KOWATCH: What are the prodromal symptoms in children and adolescents?

DR. CHANG: In the past, the earliest reported symptoms were thought to include extreme hyperactivity, inappropriate sexuality, and severe depression at a very young age (preschool or school age children). Now data point to 2 major pathways toward bipolar disorder:

• early-onset depression, which elevates risk for later mania
  
• early attention-deficit/hyperactivity disorder (ADHD).
  

DR. KOWATCH: So you’ve got a group with depression and a group with severe ADHD that might develop into bipolar disorder?

DR. CHANG: The ADHD need not be severe. In these children, ADHD may reflect an underlying brain development trajectory toward mood dysregulation. We’ve also seen anxiety as an initial condition. A cross-sectional study found anxiety to be prevalent in bipolar offspring and a possible risk factor for later mania.¹²

Anxiety is very common in children, so it’s hard to tell if it’s a precursor for bipolar disorder in an individual child. But looking back, a lot of children who develop bipolar disorder had early anxiety, which may be a marker that they were not coping well with stress. What starts leaking out as anxiety eventually may leak out as a full mood episode.

DR. CHANG: Yes, although sometimes the risk comes not from the parents but from a second-degree or more distant relative. We have seen plenty of families in which (as far as we can tell) the parents don’t have any mood disorders, but a child has full bipolar disorder that began over time—as it usually does in bipolar offspring.

Children or adolescents who have first-break episodes after very little pre-morbid dysfunction comprise yet another subset. This group tends to present with episodic manic depression.

DR. KOWATCH: Do you think children with bipolar disorder have clear mood episodes?

DR. CHANG: Our research is trying to bypass that debate. We’re trying to understand whether biomarkers in the brain or blood can be used to distinguish different types of bipolar disorders, rather than relying on symptomatology.

Related resources

• Chang KD, Howe M, Gallelli, K, Miklowitz D. Prevention of pediatric bipolar disorder: integration of neurobiological and psychosocial processes. Ann NY Acad Sci 2006;1094:235–47.
  
• Chang KD, Gallelli KA. Bipolar disorders and genetics: clinical implications of high heritability. Medscape Psychiatry & Mental Health 2004;9(2). Available at: http://www.medscape.com/viewarticle/489331.
  
• Miklowitz D, Biuckians A, Richards JA. Early-onset bipolar disorder: a family treatment perspective. Dev Psychopathol 2006;18(4):1247–65.
  

• Carbamazepine • various
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakene, Depakote
  

Dr. Chang receives research support from AstraZeneca, Eli Lilly and Company, Otsuka, and the National Institute of Mental Health. He is a consultant to Abbott Laboratories, GlaxoSmithKline, and Shire, and a speaker for Abbott Laboratories and AstraZeneca.

Dr. Kowatch receives research support from Bristol-Myers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a speaker for Abbott Laboratories and AstraZeneca.

Although it is always important to determine what other therapies a patient is taking, Dr. Joseph I. Sirven (“Dangerous duo: Antiepileptics plus herbals,” Pearls, Current Psychiatry, July 2007) betrays a lack of knowledge about botanical medicine. No herbalist prescribes water hemlock, which is not available at health food stores and has been known to be a deadly poison since the time of Socrates. Yohimbine is a drug, not a botanical, although it is derived from the yohimbe plant. St. John’s wort—which was not discussed in the article—induces the cytochrome system, especially the 3A enzymes and the multidrug resistance transporter Pglycoprotein, and should not be taken with antiepileptic drugs (AEDs).

Antispasmodic herbs such as black cohosh and kava are unlikely to induce seizures, although they might potentiate AEDs and could help to lower dosages of these medications. Ginkgo seeds are a popular food in China and Korea because cooking inactivates toxins in the seeds. Guarana acts like caffeine and may cause vasoconstriction. Ephedra, which is only available in low doses or from Chinese herbalists who use small quantities for short-term respiratory illness, has a similar effect and could possibly interact with AEDs.

I urge clinicians to obtain information about these remedies from professionals specializing in the medicinal use of herbs to improve the care of patients who use complementary and alternative medicine.

Karen S. Vaughan
Brooklyn, NY

Dr. Sirven Responds

The reader and I both believe in delivering accurate information about the use of herbals and botanicals. Although botanicals carry many promises for the treatment of neurologic and psychiatric disease, there are also a number of risks—which was the rationale for publishing a “Pearls” article on this topic.

My experience more than qualifies me to comment on herbal use. I am a practicing, epilepsy fellowship-trained, board-certified neurologist who teaches, publishes, and conducts research on antiepileptic drugs and surveys ideas on complementary and alternative medicine (CAM) use in patients with seizures and epilepsy. Apparently the reader’s passion for the topic led to several inaccuracies and mischaracterizations about the “Pearls” article. Contrary to the reader’s claims, there were no errors in the information presented.

My practice at a tertiary care epilepsy center places me in the unfortunate position of seeing serious and even fatal outcomes that result from poor clinical care with botanicals. I agree that the clinical use of botanicals should be supervised by professionals who are trained in oriental medicine and are registered herbalists, but in collaboration with neurologists, psychiatrists, and other practitioners who are charged with caring for patients with serious and refractory epilepsy and psychiatric conditions—patients likely to be taking antiepileptics.

Because the use of antiepileptic drugs and herbals has increased significantly, it is important for clinicians to understand all interactions between these 2 classes of agents. I am compelled to ensure that other practitioners are aware of potential drug interactions so that we can improve the care of patients likely to use CAM.

The last paragraph of my article notes that many patients do not tell their neurologists or other healthcare practitioners about their CAM use, and herein lies the problem. CAMs are readily available, and patients will take botanicals and herbals without professional guidance. Thus, a respectful team approach is necessary for medicine to achieve good health outcomes for all.

Joseph I. Sirven, MD
Associate professor of neurology
Mayo Clinic College of Medicine
Phoenix, AZ

Although it is always important to determine what other therapies a patient is taking, Dr. Joseph I. Sirven (“Dangerous duo: Antiepileptics plus herbals,” Pearls, Current Psychiatry, July 2007) betrays a lack of knowledge about botanical medicine. No herbalist prescribes water hemlock, which is not available at health food stores and has been known to be a deadly poison since the time of Socrates. Yohimbine is a drug, not a botanical, although it is derived from the yohimbe plant. St. John’s wort—which was not discussed in the article—induces the cytochrome system, especially the 3A enzymes and the multidrug resistance transporter Pglycoprotein, and should not be taken with antiepileptic drugs (AEDs).

Antispasmodic herbs such as black cohosh and kava are unlikely to induce seizures, although they might potentiate AEDs and could help to lower dosages of these medications. Ginkgo seeds are a popular food in China and Korea because cooking inactivates toxins in the seeds. Guarana acts like caffeine and may cause vasoconstriction. Ephedra, which is only available in low doses or from Chinese herbalists who use small quantities for short-term respiratory illness, has a similar effect and could possibly interact with AEDs.

I urge clinicians to obtain information about these remedies from professionals specializing in the medicinal use of herbs to improve the care of patients who use complementary and alternative medicine.

Karen S. Vaughan
Brooklyn, NY

Dr. Sirven Responds

The reader and I both believe in delivering accurate information about the use of herbals and botanicals. Although botanicals carry many promises for the treatment of neurologic and psychiatric disease, there are also a number of risks—which was the rationale for publishing a “Pearls” article on this topic.

My experience more than qualifies me to comment on herbal use. I am a practicing, epilepsy fellowship-trained, board-certified neurologist who teaches, publishes, and conducts research on antiepileptic drugs and surveys ideas on complementary and alternative medicine (CAM) use in patients with seizures and epilepsy. Apparently the reader’s passion for the topic led to several inaccuracies and mischaracterizations about the “Pearls” article. Contrary to the reader’s claims, there were no errors in the information presented.

My practice at a tertiary care epilepsy center places me in the unfortunate position of seeing serious and even fatal outcomes that result from poor clinical care with botanicals. I agree that the clinical use of botanicals should be supervised by professionals who are trained in oriental medicine and are registered herbalists, but in collaboration with neurologists, psychiatrists, and other practitioners who are charged with caring for patients with serious and refractory epilepsy and psychiatric conditions—patients likely to be taking antiepileptics.

Because the use of antiepileptic drugs and herbals has increased significantly, it is important for clinicians to understand all interactions between these 2 classes of agents. I am compelled to ensure that other practitioners are aware of potential drug interactions so that we can improve the care of patients likely to use CAM.

The last paragraph of my article notes that many patients do not tell their neurologists or other healthcare practitioners about their CAM use, and herein lies the problem. CAMs are readily available, and patients will take botanicals and herbals without professional guidance. Thus, a respectful team approach is necessary for medicine to achieve good health outcomes for all.

Joseph I. Sirven, MD
Associate professor of neurology
Mayo Clinic College of Medicine
Phoenix, AZ

Although it is always important to determine what other therapies a patient is taking, Dr. Joseph I. Sirven (“Dangerous duo: Antiepileptics plus herbals,” Pearls, Current Psychiatry, July 2007) betrays a lack of knowledge about botanical medicine. No herbalist prescribes water hemlock, which is not available at health food stores and has been known to be a deadly poison since the time of Socrates. Yohimbine is a drug, not a botanical, although it is derived from the yohimbe plant. St. John’s wort—which was not discussed in the article—induces the cytochrome system, especially the 3A enzymes and the multidrug resistance transporter Pglycoprotein, and should not be taken with antiepileptic drugs (AEDs).

Antispasmodic herbs such as black cohosh and kava are unlikely to induce seizures, although they might potentiate AEDs and could help to lower dosages of these medications. Ginkgo seeds are a popular food in China and Korea because cooking inactivates toxins in the seeds. Guarana acts like caffeine and may cause vasoconstriction. Ephedra, which is only available in low doses or from Chinese herbalists who use small quantities for short-term respiratory illness, has a similar effect and could possibly interact with AEDs.

I urge clinicians to obtain information about these remedies from professionals specializing in the medicinal use of herbs to improve the care of patients who use complementary and alternative medicine.

Karen S. Vaughan
Brooklyn, NY

Dr. Sirven Responds

The reader and I both believe in delivering accurate information about the use of herbals and botanicals. Although botanicals carry many promises for the treatment of neurologic and psychiatric disease, there are also a number of risks—which was the rationale for publishing a “Pearls” article on this topic.

My experience more than qualifies me to comment on herbal use. I am a practicing, epilepsy fellowship-trained, board-certified neurologist who teaches, publishes, and conducts research on antiepileptic drugs and surveys ideas on complementary and alternative medicine (CAM) use in patients with seizures and epilepsy. Apparently the reader’s passion for the topic led to several inaccuracies and mischaracterizations about the “Pearls” article. Contrary to the reader’s claims, there were no errors in the information presented.

My practice at a tertiary care epilepsy center places me in the unfortunate position of seeing serious and even fatal outcomes that result from poor clinical care with botanicals. I agree that the clinical use of botanicals should be supervised by professionals who are trained in oriental medicine and are registered herbalists, but in collaboration with neurologists, psychiatrists, and other practitioners who are charged with caring for patients with serious and refractory epilepsy and psychiatric conditions—patients likely to be taking antiepileptics.

Because the use of antiepileptic drugs and herbals has increased significantly, it is important for clinicians to understand all interactions between these 2 classes of agents. I am compelled to ensure that other practitioners are aware of potential drug interactions so that we can improve the care of patients likely to use CAM.

The last paragraph of my article notes that many patients do not tell their neurologists or other healthcare practitioners about their CAM use, and herein lies the problem. CAMs are readily available, and patients will take botanicals and herbals without professional guidance. Thus, a respectful team approach is necessary for medicine to achieve good health outcomes for all.

Joseph I. Sirven, MD
Associate professor of neurology
Mayo Clinic College of Medicine
Phoenix, AZ

With nearly 30,000 organ transplants being performed in the United States each year (Box 1),¹ demand is growing for psychiatrists to provide presurgical and ongoing care.

How you might collaborate with a transplant team depends on each medical center’s protocols and individual patients’ mental health needs. A transplant candidate with depressive or anxiety symptoms may be referred to you for presurgical stabilization, for example, particularly if the patient lives far from a highly specialized transplant center.

Transplant assessments differ from usual psychiatric evaluations. Your findings will be used to help the transplant team evaluate the patient’s demographics, disease severity, and resources to give the patient the best chance for medical recovery. Inform patients at the beginning of the pretransplant evaluation that the results:

• will be shared with the transplant team
• may be used to help make decisions about transplant
• will not be the only factor determining if a transplant center will place a patient on an organ wait list.²

Pretransplant evaluation

Presurgical assessment helps determine the patient’s understanding of the transplant process and ability to provide consent (Table 1).³ Patients do not need a high level of medical sophistication to discuss transplantation, but they must understand the basics of the procedure and be able to rationally discuss their options. If a patient has severe cognitive impairment, dementia, or hepatic encephalopathy and cannot participate in the consent process, a surrogate is necessary.

Explore the patient’s attitudes and beliefs about transplant. If other team members have educated the patient about the procedure, your assessment can help determine how much the patient understood and if the patient has the capacity to make treatment decisions. Some patients believe the operation will “cure” them, despite education about the rigorous posttransplant routine. Alert the transplant team to these views, and begin aligning the patient’s views with reality.

Box 1

Table 1

Psychiatric assessment of the pretransplant patient

Assessing psychiatric comorbidity. Like other patients with life-threatening medical illnesses, many transplant patients present with major depression and anxiety. Screen for symptoms of mood and anxiety disorders and past episodes of depression or mania. Explore the patient’s response to psychiatric treatment, current therapies, and history of treatment adherence.

Depression. Patients listed for transplant are seriously ill and coping with the difficulties of the sick role. Organ failure symptoms and resultant disability—such as insomnia, anorexia, fatigue, and impaired concentration—overlap with depression’s neurovegetative signs. Suspect depression if a patient presents with anhedonia, tearfulness, apathy, or guilt.

Among heart, lung, and liver transplant candidates, the reported lifetime prevalence of depression averages approximately 20%.^4-6

Anxiety disorders. An estimated 40% of transplant patients have anxiety disorders,⁷ which may be caused by:

• stress of chronic illness
• uncertainty of the transplant process
• medical conditions such as hypothyroidism or pulmonary embolism.

Chronic mental illness. Patients with major mental illnesses such as schizophrenia might be appropriate candidates for organ transplant if they have adequate social support and history of treatment compliance.

Pharmacotherapy. Because of the variety of medical problems seen in transplant candidates, carefully consider medication side effects and drug-drug interactions when prescribing psychotropics.

Antidepressants. Among the selective serotonin reuptake inhibitors (SSRIs), citalopram, escitalopram, and sertraline are least likely to affect hepatic metabolism of other medications (Table 2).⁸ If a patient presents with liver failure, reduce the dosages of medications with hepatic metabolism.

Benzodiazepines. Use caution when treating anxiety with benzodiazepines because of the risk of tolerance, withdrawal, and dependence. Avoid benzodiazepines when treating transplant candidates with a substance abuse history. Also, these drugs might worsen hepatic encephalopathy and increase confusion.

Patients awaiting lung transplantation, especially those with high levels of CO₂ retention, require special care because benzodiazepines might decrease respiratory drive. Try other agents such as buspirone, gabapentin, SSRIs, or second-generation antipsychotics to treat their anxiety.

Psychotherapy. Supportive psychotherapy can help patients navigate the often-lengthy process of waiting for a donor organ. Support groups for organ transplant candidates may help ease patients’ depressive symptoms.

Table 2

Antidepressants’ half-life and effect on hepatic metabolism

Assessing substance abuse

Up to 50% of liver transplant candidates have a history of alcohol and/or drug abuse,⁹ the highest rate among transplant populations. Alcohol-induced cirrhosis and hepatitis C contracted from IV drug use are common indications for liver transplant. Effective treatment of substance abuse is essential because 30% to 50% of these patients relapse after the procedure.¹⁰ Assess:

• each substance abused, including onset, peak, and current use
• family history of substance abuse disorders
• past efforts at rehabilitation
• tobacco use (smoking before and after transplant is related to an increased incidence of new cancer diagnoses).¹¹

Some transplant centers require patients with substance
use disorders to participate in 12-step programs or
rehabilitation. Regardless of the institutions’
requirements, encourage patients to participate in
rehabilitation to prevent relapse and mitigate the
negative impact of substance abuse on physical
and mental well-being.

Mental status examination includes the usual elements such as appearance, behavior, speech, affect, and thought process. Assess for suicidal thinking or hopelessness, which have been linked to serious medical illness.¹² Question patients about hallucinations and give special attention to visual aberrations, which may occur in medically ill patients.

Cognitive testing. Use tools such as the Mini-Mental State Examination, clock drawing test, and Trail Making A and B tests to assess cognitive ability. If patients show signs of cognitive impairment, arrange for follow-up examinations and refer for neuropsychological testing.

Some cognitive impairment—such as that caused by hepatic encephalopathy—will likely improve after transplant, but other types—such as that caused by vascular disease—will not. If confusion is caused by hepatic encephalopathy, treatment with lactulose might rapidly improve symptoms. Remember that patients with hepatic encephalopathy might not exhibit elevated ammonia levels. Underlying causes of worsening hepatic encephalopathy—such as infections or bleeding—might require treatment.

Assessing adherence. Medication adherence after transplant is essential to prevent organ rejection and other complications. Posttransplant regimens are complex, and the frequency of follow-up assessments can be intense—particularly in the first year after transplant.

Your pretransplant assessment can identify where patients have struggled with adherence in the past. Before the transplant, your team can work to correct barriers such as inability to pay for medications, child care problems, or transportation needs.

Personality disorders have been identified as predictors of posttransplant nonadherence, and 50% to 60% of transplant programs consider personality disorders a relative contraindication to organ transplant.¹³ Address other contributors to poor adherence—such as substance abuse or depression—with ongoing psychiatric care.

Box 2

Social support is essential to help with the normal difficulties such as frequent clinic visits and initial physical disability patients face after successful transplant (Box 2). Ask about the candidate’s family, friends, spirituality, and finances during your pretransplant assessment. Poor social support is related to the development of posttransplant psychiatric disorders¹⁴ and adherence difficulties.¹⁵

Assessment instruments—such as the Psychosocial Assessment of Candidates for Transplantation and the Transplant Evaluation Rating Scale³—include social support items and can be useful in identifying weak areas.

Data collected by other team members can be invaluable. A nurse or social worker, for example, may observe that a patient is unwilling to take medications, contrary to the patient’s report. Other sources of information include the patient’s family and friends, a primary care physician, or other mental health providers such as a therapist or case manager.

Posttransplant psychiatric care

Depression. The incidence of depression is higher in the year following transplant than before transplant or in the immediate posttransplant period.⁵ Predictors of posttransplant depression include:

• history of depression
• poor social support
• passive coping strategies
• poor physical status after transplantation.^16,17

Carefully monitor patients who present with these factors after transplant. Treat depression with supportive measures designed to improve the patient’s social network and coping skills and pharmacotherapy. Select antidepressant medications based on side effect profiles and impact on the patient’s transplanted organs.

Substance abuse. Patients with a pretransplant history of substance abuse often relapse. Among transplant recipients with a history of alcoholic liver disease, drinking rates of 30% to 40% have been reported 5 years after transplant. Most of these data represent occasional use, not heavy or regular drinking.¹⁸ Relapse can occur despite careful assessment and follow-up.

Some evidence suggests that transplant patients who resume drinking have worse outcomes than those who abstain. Alcoholism relapse has other negative consequences, such as relationship problems and employment difficulties.

Predictors of relapse include:

• pretransplant history of alcohol dependence
• family history of alcoholism
• rehabilitation history, which could indicate a severe substance abuse disorder.³

Medications for alcoholism treatment have not been studied systematically in transplant patients, but low doses of acamprosate, ≤2 g/d, and naltrexone, ≤200 mg/d, are options for patients interested in pharmacotherapy. Support from 12-step programs also helps treat substance-abusing patients.

Altered mental status. Immunosuppressive medications—including cyclosporine, tacrolimus, and prednisone—can have neuropsychiatric effects and could cause a change in mental status (Table 3).¹⁹ Check cyclosporine and tacrolimus serum levels against reference ranges when delirium is present. If levels are toxic the dosage often can be lowered, which might lead to clinical improvement.

Quality of life. In general, patients’ quality of life improves after their transplant. After the first year—which patients might find difficult because of changes in physical and social status—quality of life typically improves.⁵

Table 3

Neuropsychiatric side effects of medications
commonly used in transplant patients

Psychiatric disorders such as depression can worsen quality of life. However, quality of life can improve after depression is diagnosed and treated. Other predictors of improved quality of life include older age, marriage, and the absence of a personality disorder.⁴

Other posttransplant concerns of patients include changes in employment, finances, and relationships. Patients often have been away from work before transplant, and returning after a long absence can be stressful. Patients may find that they cannot work as well as before becoming ill, which may lead to frustration, depression, and/or anxiety symptoms. Transplant surgery requires a large financial investment, and money concerns usually persist long after the transplant.

The transplant recipient’s role within the family may shift after surgery. Families might expect the patient to “return to normal” and resume old activities. Alternatively, family members might continue to treat the patient as a person with chronic illness despite physical improvement. If patients are struggling with these changes, supportive psychotherapy is indicated.

Related resource

• United Network for Organ Sharing. www.unos.org.
• Transplant living. www.transplantliving.org.
• Trzepacz PT, DiMartini AF, eds. The transplant patient. Cambridge, UK: Cambridge University Press; 2000.
• Klapheke MM. The role of the psychiatrist in organ transplantation. Bull Menninger Clin 1999;63(1):13-39.

Drug brand names

• Acamprosate • Campral
• Buspirone • BuSpar
• Bupropion SR • Wellbutrin SR
• Citalopram • Celexa
• Cyclosporine • Sandimmune
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lactulose • Cephulac, Chronulac
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Paroxetine • Paxil
• Prednisone • Deltasone
• Sertraline • Zoloft
• Tacrolimus • Prograf
• Trazodone • Desyrel

Disclosure

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

With nearly 30,000 organ transplants being performed in the United States each year (Box 1),¹ demand is growing for psychiatrists to provide presurgical and ongoing care.

How you might collaborate with a transplant team depends on each medical center’s protocols and individual patients’ mental health needs. A transplant candidate with depressive or anxiety symptoms may be referred to you for presurgical stabilization, for example, particularly if the patient lives far from a highly specialized transplant center.

Transplant assessments differ from usual psychiatric evaluations. Your findings will be used to help the transplant team evaluate the patient’s demographics, disease severity, and resources to give the patient the best chance for medical recovery. Inform patients at the beginning of the pretransplant evaluation that the results:

• will be shared with the transplant team
• may be used to help make decisions about transplant
• will not be the only factor determining if a transplant center will place a patient on an organ wait list.²

Pretransplant evaluation

Presurgical assessment helps determine the patient’s understanding of the transplant process and ability to provide consent (Table 1).³ Patients do not need a high level of medical sophistication to discuss transplantation, but they must understand the basics of the procedure and be able to rationally discuss their options. If a patient has severe cognitive impairment, dementia, or hepatic encephalopathy and cannot participate in the consent process, a surrogate is necessary.

Explore the patient’s attitudes and beliefs about transplant. If other team members have educated the patient about the procedure, your assessment can help determine how much the patient understood and if the patient has the capacity to make treatment decisions. Some patients believe the operation will “cure” them, despite education about the rigorous posttransplant routine. Alert the transplant team to these views, and begin aligning the patient’s views with reality.

Box 1

Table 1

Psychiatric assessment of the pretransplant patient

Assessing psychiatric comorbidity. Like other patients with life-threatening medical illnesses, many transplant patients present with major depression and anxiety. Screen for symptoms of mood and anxiety disorders and past episodes of depression or mania. Explore the patient’s response to psychiatric treatment, current therapies, and history of treatment adherence.

Depression. Patients listed for transplant are seriously ill and coping with the difficulties of the sick role. Organ failure symptoms and resultant disability—such as insomnia, anorexia, fatigue, and impaired concentration—overlap with depression’s neurovegetative signs. Suspect depression if a patient presents with anhedonia, tearfulness, apathy, or guilt.

Among heart, lung, and liver transplant candidates, the reported lifetime prevalence of depression averages approximately 20%.^4-6

Anxiety disorders. An estimated 40% of transplant patients have anxiety disorders,⁷ which may be caused by:

• stress of chronic illness
• uncertainty of the transplant process
• medical conditions such as hypothyroidism or pulmonary embolism.

Chronic mental illness. Patients with major mental illnesses such as schizophrenia might be appropriate candidates for organ transplant if they have adequate social support and history of treatment compliance.

Pharmacotherapy. Because of the variety of medical problems seen in transplant candidates, carefully consider medication side effects and drug-drug interactions when prescribing psychotropics.

Antidepressants. Among the selective serotonin reuptake inhibitors (SSRIs), citalopram, escitalopram, and sertraline are least likely to affect hepatic metabolism of other medications (Table 2).⁸ If a patient presents with liver failure, reduce the dosages of medications with hepatic metabolism.

Benzodiazepines. Use caution when treating anxiety with benzodiazepines because of the risk of tolerance, withdrawal, and dependence. Avoid benzodiazepines when treating transplant candidates with a substance abuse history. Also, these drugs might worsen hepatic encephalopathy and increase confusion.

Patients awaiting lung transplantation, especially those with high levels of CO₂ retention, require special care because benzodiazepines might decrease respiratory drive. Try other agents such as buspirone, gabapentin, SSRIs, or second-generation antipsychotics to treat their anxiety.

Psychotherapy. Supportive psychotherapy can help patients navigate the often-lengthy process of waiting for a donor organ. Support groups for organ transplant candidates may help ease patients’ depressive symptoms.

Table 2

Antidepressants’ half-life and effect on hepatic metabolism

Assessing substance abuse

Up to 50% of liver transplant candidates have a history of alcohol and/or drug abuse,⁹ the highest rate among transplant populations. Alcohol-induced cirrhosis and hepatitis C contracted from IV drug use are common indications for liver transplant. Effective treatment of substance abuse is essential because 30% to 50% of these patients relapse after the procedure.¹⁰ Assess:

• each substance abused, including onset, peak, and current use
• family history of substance abuse disorders
• past efforts at rehabilitation
• tobacco use (smoking before and after transplant is related to an increased incidence of new cancer diagnoses).¹¹

Some transplant centers require patients with substance
use disorders to participate in 12-step programs or
rehabilitation. Regardless of the institutions’
requirements, encourage patients to participate in
rehabilitation to prevent relapse and mitigate the
negative impact of substance abuse on physical
and mental well-being.

Mental status examination includes the usual elements such as appearance, behavior, speech, affect, and thought process. Assess for suicidal thinking or hopelessness, which have been linked to serious medical illness.¹² Question patients about hallucinations and give special attention to visual aberrations, which may occur in medically ill patients.

Cognitive testing. Use tools such as the Mini-Mental State Examination, clock drawing test, and Trail Making A and B tests to assess cognitive ability. If patients show signs of cognitive impairment, arrange for follow-up examinations and refer for neuropsychological testing.

Some cognitive impairment—such as that caused by hepatic encephalopathy—will likely improve after transplant, but other types—such as that caused by vascular disease—will not. If confusion is caused by hepatic encephalopathy, treatment with lactulose might rapidly improve symptoms. Remember that patients with hepatic encephalopathy might not exhibit elevated ammonia levels. Underlying causes of worsening hepatic encephalopathy—such as infections or bleeding—might require treatment.

Assessing adherence. Medication adherence after transplant is essential to prevent organ rejection and other complications. Posttransplant regimens are complex, and the frequency of follow-up assessments can be intense—particularly in the first year after transplant.

Your pretransplant assessment can identify where patients have struggled with adherence in the past. Before the transplant, your team can work to correct barriers such as inability to pay for medications, child care problems, or transportation needs.

Personality disorders have been identified as predictors of posttransplant nonadherence, and 50% to 60% of transplant programs consider personality disorders a relative contraindication to organ transplant.¹³ Address other contributors to poor adherence—such as substance abuse or depression—with ongoing psychiatric care.

Box 2

Social support is essential to help with the normal difficulties such as frequent clinic visits and initial physical disability patients face after successful transplant (Box 2). Ask about the candidate’s family, friends, spirituality, and finances during your pretransplant assessment. Poor social support is related to the development of posttransplant psychiatric disorders¹⁴ and adherence difficulties.¹⁵

Assessment instruments—such as the Psychosocial Assessment of Candidates for Transplantation and the Transplant Evaluation Rating Scale³—include social support items and can be useful in identifying weak areas.

Data collected by other team members can be invaluable. A nurse or social worker, for example, may observe that a patient is unwilling to take medications, contrary to the patient’s report. Other sources of information include the patient’s family and friends, a primary care physician, or other mental health providers such as a therapist or case manager.

Posttransplant psychiatric care

Depression. The incidence of depression is higher in the year following transplant than before transplant or in the immediate posttransplant period.⁵ Predictors of posttransplant depression include:

• history of depression
• poor social support
• passive coping strategies
• poor physical status after transplantation.^16,17

Carefully monitor patients who present with these factors after transplant. Treat depression with supportive measures designed to improve the patient’s social network and coping skills and pharmacotherapy. Select antidepressant medications based on side effect profiles and impact on the patient’s transplanted organs.

Substance abuse. Patients with a pretransplant history of substance abuse often relapse. Among transplant recipients with a history of alcoholic liver disease, drinking rates of 30% to 40% have been reported 5 years after transplant. Most of these data represent occasional use, not heavy or regular drinking.¹⁸ Relapse can occur despite careful assessment and follow-up.

Some evidence suggests that transplant patients who resume drinking have worse outcomes than those who abstain. Alcoholism relapse has other negative consequences, such as relationship problems and employment difficulties.

Predictors of relapse include:

• pretransplant history of alcohol dependence
• family history of alcoholism
• rehabilitation history, which could indicate a severe substance abuse disorder.³

Medications for alcoholism treatment have not been studied systematically in transplant patients, but low doses of acamprosate, ≤2 g/d, and naltrexone, ≤200 mg/d, are options for patients interested in pharmacotherapy. Support from 12-step programs also helps treat substance-abusing patients.

Altered mental status. Immunosuppressive medications—including cyclosporine, tacrolimus, and prednisone—can have neuropsychiatric effects and could cause a change in mental status (Table 3).¹⁹ Check cyclosporine and tacrolimus serum levels against reference ranges when delirium is present. If levels are toxic the dosage often can be lowered, which might lead to clinical improvement.

Quality of life. In general, patients’ quality of life improves after their transplant. After the first year—which patients might find difficult because of changes in physical and social status—quality of life typically improves.⁵

Table 3

Neuropsychiatric side effects of medications
commonly used in transplant patients

Psychiatric disorders such as depression can worsen quality of life. However, quality of life can improve after depression is diagnosed and treated. Other predictors of improved quality of life include older age, marriage, and the absence of a personality disorder.⁴

Other posttransplant concerns of patients include changes in employment, finances, and relationships. Patients often have been away from work before transplant, and returning after a long absence can be stressful. Patients may find that they cannot work as well as before becoming ill, which may lead to frustration, depression, and/or anxiety symptoms. Transplant surgery requires a large financial investment, and money concerns usually persist long after the transplant.

The transplant recipient’s role within the family may shift after surgery. Families might expect the patient to “return to normal” and resume old activities. Alternatively, family members might continue to treat the patient as a person with chronic illness despite physical improvement. If patients are struggling with these changes, supportive psychotherapy is indicated.

Related resource

• United Network for Organ Sharing. www.unos.org.
• Transplant living. www.transplantliving.org.
• Trzepacz PT, DiMartini AF, eds. The transplant patient. Cambridge, UK: Cambridge University Press; 2000.
• Klapheke MM. The role of the psychiatrist in organ transplantation. Bull Menninger Clin 1999;63(1):13-39.

Drug brand names

• Acamprosate • Campral
• Buspirone • BuSpar
• Bupropion SR • Wellbutrin SR
• Citalopram • Celexa
• Cyclosporine • Sandimmune
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lactulose • Cephulac, Chronulac
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Paroxetine • Paxil
• Prednisone • Deltasone
• Sertraline • Zoloft
• Tacrolimus • Prograf
• Trazodone • Desyrel

Disclosure

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

With nearly 30,000 organ transplants being performed in the United States each year (Box 1),¹ demand is growing for psychiatrists to provide presurgical and ongoing care.

How you might collaborate with a transplant team depends on each medical center’s protocols and individual patients’ mental health needs. A transplant candidate with depressive or anxiety symptoms may be referred to you for presurgical stabilization, for example, particularly if the patient lives far from a highly specialized transplant center.

Transplant assessments differ from usual psychiatric evaluations. Your findings will be used to help the transplant team evaluate the patient’s demographics, disease severity, and resources to give the patient the best chance for medical recovery. Inform patients at the beginning of the pretransplant evaluation that the results:

• will be shared with the transplant team
• may be used to help make decisions about transplant
• will not be the only factor determining if a transplant center will place a patient on an organ wait list.²

Pretransplant evaluation

Presurgical assessment helps determine the patient’s understanding of the transplant process and ability to provide consent (Table 1).³ Patients do not need a high level of medical sophistication to discuss transplantation, but they must understand the basics of the procedure and be able to rationally discuss their options. If a patient has severe cognitive impairment, dementia, or hepatic encephalopathy and cannot participate in the consent process, a surrogate is necessary.

Explore the patient’s attitudes and beliefs about transplant. If other team members have educated the patient about the procedure, your assessment can help determine how much the patient understood and if the patient has the capacity to make treatment decisions. Some patients believe the operation will “cure” them, despite education about the rigorous posttransplant routine. Alert the transplant team to these views, and begin aligning the patient’s views with reality.

Box 1

Table 1

Psychiatric assessment of the pretransplant patient

Assessing psychiatric comorbidity. Like other patients with life-threatening medical illnesses, many transplant patients present with major depression and anxiety. Screen for symptoms of mood and anxiety disorders and past episodes of depression or mania. Explore the patient’s response to psychiatric treatment, current therapies, and history of treatment adherence.

Depression. Patients listed for transplant are seriously ill and coping with the difficulties of the sick role. Organ failure symptoms and resultant disability—such as insomnia, anorexia, fatigue, and impaired concentration—overlap with depression’s neurovegetative signs. Suspect depression if a patient presents with anhedonia, tearfulness, apathy, or guilt.

Among heart, lung, and liver transplant candidates, the reported lifetime prevalence of depression averages approximately 20%.^4-6

Anxiety disorders. An estimated 40% of transplant patients have anxiety disorders,⁷ which may be caused by:

• stress of chronic illness
• uncertainty of the transplant process
• medical conditions such as hypothyroidism or pulmonary embolism.

Chronic mental illness. Patients with major mental illnesses such as schizophrenia might be appropriate candidates for organ transplant if they have adequate social support and history of treatment compliance.

Pharmacotherapy. Because of the variety of medical problems seen in transplant candidates, carefully consider medication side effects and drug-drug interactions when prescribing psychotropics.

Antidepressants. Among the selective serotonin reuptake inhibitors (SSRIs), citalopram, escitalopram, and sertraline are least likely to affect hepatic metabolism of other medications (Table 2).⁸ If a patient presents with liver failure, reduce the dosages of medications with hepatic metabolism.

Benzodiazepines. Use caution when treating anxiety with benzodiazepines because of the risk of tolerance, withdrawal, and dependence. Avoid benzodiazepines when treating transplant candidates with a substance abuse history. Also, these drugs might worsen hepatic encephalopathy and increase confusion.

Patients awaiting lung transplantation, especially those with high levels of CO₂ retention, require special care because benzodiazepines might decrease respiratory drive. Try other agents such as buspirone, gabapentin, SSRIs, or second-generation antipsychotics to treat their anxiety.

Psychotherapy. Supportive psychotherapy can help patients navigate the often-lengthy process of waiting for a donor organ. Support groups for organ transplant candidates may help ease patients’ depressive symptoms.

Table 2

Antidepressants’ half-life and effect on hepatic metabolism

Assessing substance abuse

Up to 50% of liver transplant candidates have a history of alcohol and/or drug abuse,⁹ the highest rate among transplant populations. Alcohol-induced cirrhosis and hepatitis C contracted from IV drug use are common indications for liver transplant. Effective treatment of substance abuse is essential because 30% to 50% of these patients relapse after the procedure.¹⁰ Assess:

• each substance abused, including onset, peak, and current use
• family history of substance abuse disorders
• past efforts at rehabilitation
• tobacco use (smoking before and after transplant is related to an increased incidence of new cancer diagnoses).¹¹

Some transplant centers require patients with substance
use disorders to participate in 12-step programs or
rehabilitation. Regardless of the institutions’
requirements, encourage patients to participate in
rehabilitation to prevent relapse and mitigate the
negative impact of substance abuse on physical
and mental well-being.

Mental status examination includes the usual elements such as appearance, behavior, speech, affect, and thought process. Assess for suicidal thinking or hopelessness, which have been linked to serious medical illness.¹² Question patients about hallucinations and give special attention to visual aberrations, which may occur in medically ill patients.

Cognitive testing. Use tools such as the Mini-Mental State Examination, clock drawing test, and Trail Making A and B tests to assess cognitive ability. If patients show signs of cognitive impairment, arrange for follow-up examinations and refer for neuropsychological testing.

Some cognitive impairment—such as that caused by hepatic encephalopathy—will likely improve after transplant, but other types—such as that caused by vascular disease—will not. If confusion is caused by hepatic encephalopathy, treatment with lactulose might rapidly improve symptoms. Remember that patients with hepatic encephalopathy might not exhibit elevated ammonia levels. Underlying causes of worsening hepatic encephalopathy—such as infections or bleeding—might require treatment.

Assessing adherence. Medication adherence after transplant is essential to prevent organ rejection and other complications. Posttransplant regimens are complex, and the frequency of follow-up assessments can be intense—particularly in the first year after transplant.

Your pretransplant assessment can identify where patients have struggled with adherence in the past. Before the transplant, your team can work to correct barriers such as inability to pay for medications, child care problems, or transportation needs.

Personality disorders have been identified as predictors of posttransplant nonadherence, and 50% to 60% of transplant programs consider personality disorders a relative contraindication to organ transplant.¹³ Address other contributors to poor adherence—such as substance abuse or depression—with ongoing psychiatric care.

Box 2

Social support is essential to help with the normal difficulties such as frequent clinic visits and initial physical disability patients face after successful transplant (Box 2). Ask about the candidate’s family, friends, spirituality, and finances during your pretransplant assessment. Poor social support is related to the development of posttransplant psychiatric disorders¹⁴ and adherence difficulties.¹⁵

Assessment instruments—such as the Psychosocial Assessment of Candidates for Transplantation and the Transplant Evaluation Rating Scale³—include social support items and can be useful in identifying weak areas.

Data collected by other team members can be invaluable. A nurse or social worker, for example, may observe that a patient is unwilling to take medications, contrary to the patient’s report. Other sources of information include the patient’s family and friends, a primary care physician, or other mental health providers such as a therapist or case manager.

Posttransplant psychiatric care

Depression. The incidence of depression is higher in the year following transplant than before transplant or in the immediate posttransplant period.⁵ Predictors of posttransplant depression include:

• history of depression
• poor social support
• passive coping strategies
• poor physical status after transplantation.^16,17

Carefully monitor patients who present with these factors after transplant. Treat depression with supportive measures designed to improve the patient’s social network and coping skills and pharmacotherapy. Select antidepressant medications based on side effect profiles and impact on the patient’s transplanted organs.

Substance abuse. Patients with a pretransplant history of substance abuse often relapse. Among transplant recipients with a history of alcoholic liver disease, drinking rates of 30% to 40% have been reported 5 years after transplant. Most of these data represent occasional use, not heavy or regular drinking.¹⁸ Relapse can occur despite careful assessment and follow-up.

Some evidence suggests that transplant patients who resume drinking have worse outcomes than those who abstain. Alcoholism relapse has other negative consequences, such as relationship problems and employment difficulties.

Predictors of relapse include:

• pretransplant history of alcohol dependence
• family history of alcoholism
• rehabilitation history, which could indicate a severe substance abuse disorder.³

Medications for alcoholism treatment have not been studied systematically in transplant patients, but low doses of acamprosate, ≤2 g/d, and naltrexone, ≤200 mg/d, are options for patients interested in pharmacotherapy. Support from 12-step programs also helps treat substance-abusing patients.

Altered mental status. Immunosuppressive medications—including cyclosporine, tacrolimus, and prednisone—can have neuropsychiatric effects and could cause a change in mental status (Table 3).¹⁹ Check cyclosporine and tacrolimus serum levels against reference ranges when delirium is present. If levels are toxic the dosage often can be lowered, which might lead to clinical improvement.

Quality of life. In general, patients’ quality of life improves after their transplant. After the first year—which patients might find difficult because of changes in physical and social status—quality of life typically improves.⁵

Table 3

Neuropsychiatric side effects of medications
commonly used in transplant patients

Psychiatric disorders such as depression can worsen quality of life. However, quality of life can improve after depression is diagnosed and treated. Other predictors of improved quality of life include older age, marriage, and the absence of a personality disorder.⁴

Other posttransplant concerns of patients include changes in employment, finances, and relationships. Patients often have been away from work before transplant, and returning after a long absence can be stressful. Patients may find that they cannot work as well as before becoming ill, which may lead to frustration, depression, and/or anxiety symptoms. Transplant surgery requires a large financial investment, and money concerns usually persist long after the transplant.

The transplant recipient’s role within the family may shift after surgery. Families might expect the patient to “return to normal” and resume old activities. Alternatively, family members might continue to treat the patient as a person with chronic illness despite physical improvement. If patients are struggling with these changes, supportive psychotherapy is indicated.

Related resource

• United Network for Organ Sharing. www.unos.org.
• Transplant living. www.transplantliving.org.
• Trzepacz PT, DiMartini AF, eds. The transplant patient. Cambridge, UK: Cambridge University Press; 2000.
• Klapheke MM. The role of the psychiatrist in organ transplantation. Bull Menninger Clin 1999;63(1):13-39.

Drug brand names

• Acamprosate • Campral
• Buspirone • BuSpar
• Bupropion SR • Wellbutrin SR
• Citalopram • Celexa
• Cyclosporine • Sandimmune
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lactulose • Cephulac, Chronulac
• Mirtazapine • Remeron
• Naltrexone • ReVia
• Paroxetine • Paxil
• Prednisone • Deltasone
• Sertraline • Zoloft
• Tacrolimus • Prograf
• Trazodone • Desyrel

Disclosure

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

A font problem resulted in several symbols being omitted from Figures 1 and 2 in the article, “Can you interpret confidence intervals? It’s not that difficult” (Current Psychiatry, August 2007).

In Figure 1, the y-axis should have included a positive infinity symbol at the top and a negative infinity symbol at the bottom. In Figure 2, an infinity symbol should have been included at the center of the y-axis.

A font problem resulted in several symbols being omitted from Figures 1 and 2 in the article, “Can you interpret confidence intervals? It’s not that difficult” (Current Psychiatry, August 2007).

In Figure 1, the y-axis should have included a positive infinity symbol at the top and a negative infinity symbol at the bottom. In Figure 2, an infinity symbol should have been included at the center of the y-axis.

A font problem resulted in several symbols being omitted from Figures 1 and 2 in the article, “Can you interpret confidence intervals? It’s not that difficult” (Current Psychiatry, August 2007).

In Figure 1, the y-axis should have included a positive infinity symbol at the top and a negative infinity symbol at the bottom. In Figure 2, an infinity symbol should have been included at the center of the y-axis.