I am rebutting “How to reduce aggression in patients with conduct disorder” (Current Psychiatry, April 2004).

A 15-year-old ended his first two visits with me under police custody and was committed both times. After the first commitment, his grandmother filed a petition alleging unruly/delinquent behavior, and a judge ordered the boy to take his prescribed mood stabilizers. That was necessary because the hospital psychiatrist had determined that the boy was not mentally ill and that his grandmother needed parenting classes. The youth’s original diagnosis—conduct disorder and oppositional-defiant disorder (ODD)—contradicted my diagnosis: bipolar disorder, mixed.

During the second hospitalization, a psychiatrist diagnosed the youth as having attentiondeficit/hyperactivity disorder (ADHD). The doctor prescribed methylphenidate and oxcarbazepine, but the patient’s guardian did not consent to the medications.

Facing a sentence at the county juvenile detention center, the youth started taking olanzapine, 10 mg at bedtime, and lamotrigine, 25 mg bid titrated to 50 mg bid, as I had prescribed. His grandmother says that he no longer exhibits defiant behavior. At his third visit, he shook my hand and said, “Thank you for finding the right medications for me.”

I have seen hundreds of similar cases over 10 years. To paraphrase a colleague, diagnosing somebody with conduct disorder or ODD is like diagnosing a patient with a runny nose after a thorough emergency room examination.

I applaud the American Association of Community Psychiatry’s efforts to urge the American Psychiatric Association (APA) to abolish the conduct disorder diagnosis. I also support the many researchers who are requesting elimination of conduct disorder and ODD. These are not real and specific diagnoses but are alleged syndromes that express several conditions.

Manuel Mota-Castillo MD
Orlando, FL

Dr. Malone responds

It is hard to assess Dr. Mota-Castillo’s case based on the information he provided. Still, one would not refute any psychiatric syndrome by citing a single case.

Most psychiatric disorders are syndromes and affect heterogeneous groups. This is true for disorders that are more prevalent in adults—such as schizophrenia and mania—and for those that present in childhood and adolescence—such as conduct disorder, ODD, and ADHD. Heterogeneity within disorders is no doubt related to underlying individual differences in genetics and environment and contributes to differences in symptom expression and treatment response.

Dr. Mota-Castillo did not present symptoms listed under DSM-IV-TR, so it is unclear how the patient was diagnosed. Diagnoses:

• are one clinician’s impression or the consensus of several clinicians
• are based on one patient encounter or ongoing treatment
• occur with or without input from other sources, such as parents and school
• are made with or without validated structured interviews.

Conduct disorder and ODDare part of DSM diagnostic nomenclature,¹ and the APA and American Academy of Child and Adolescent Psychiatry recognize both disorders. Reducing aggression associated with either disorder has long been the most common reason for psychiatric consultation in children.²

Also, Dr. Mota-Castillo prescribed olanzapine and lamotrigine, apparently for simultaneous use. The main point of our case was to discourage polypharmacy—something most experts agree should be avoided³ —by carefully starting one drug before adding a second. When a child receives two drugs at once, we cannot know the effect of either.

In the 15-year-old’s case, as often happens, the prescribed treatment might not have changed the symptoms; some symptoms remit spontaneously.

Nor does drug response clarify diagnosis. For example, both bipolar disorder and aggression in conduct disorder (and in many other conditions) may respond to an antipsychotic.⁴ Lithium and other treatments for mania have been shown to reduce severe aggression in nonmanic children and adolescents with conduct disorder.^5,6

Richard P. Malone, MD
Associate professor
Eastern Pennsylvania Psychiatric Institute
Drexel University College of Medicine
Philadelphia, PA

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed-rev). Washington, DC: American Psychiatric Association, 2000.
2. Kazdin AE. Conduct disorders in childhood and adolescence, vol. 9: developmental clinical psychology and psychiatry series. Newbury Park, CA: Sage Publications, 1987.
3. Pappadopulos E, Macintyre JC II, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY): Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145–61.
4. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment.New York: Marcel Dekker, 2003:331–49.
5. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000;57(7):649–54.
6. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34(4):445–53.

I am rebutting “How to reduce aggression in patients with conduct disorder” (Current Psychiatry, April 2004).

A 15-year-old ended his first two visits with me under police custody and was committed both times. After the first commitment, his grandmother filed a petition alleging unruly/delinquent behavior, and a judge ordered the boy to take his prescribed mood stabilizers. That was necessary because the hospital psychiatrist had determined that the boy was not mentally ill and that his grandmother needed parenting classes. The youth’s original diagnosis—conduct disorder and oppositional-defiant disorder (ODD)—contradicted my diagnosis: bipolar disorder, mixed.

During the second hospitalization, a psychiatrist diagnosed the youth as having attentiondeficit/hyperactivity disorder (ADHD). The doctor prescribed methylphenidate and oxcarbazepine, but the patient’s guardian did not consent to the medications.

Facing a sentence at the county juvenile detention center, the youth started taking olanzapine, 10 mg at bedtime, and lamotrigine, 25 mg bid titrated to 50 mg bid, as I had prescribed. His grandmother says that he no longer exhibits defiant behavior. At his third visit, he shook my hand and said, “Thank you for finding the right medications for me.”

I have seen hundreds of similar cases over 10 years. To paraphrase a colleague, diagnosing somebody with conduct disorder or ODD is like diagnosing a patient with a runny nose after a thorough emergency room examination.

I applaud the American Association of Community Psychiatry’s efforts to urge the American Psychiatric Association (APA) to abolish the conduct disorder diagnosis. I also support the many researchers who are requesting elimination of conduct disorder and ODD. These are not real and specific diagnoses but are alleged syndromes that express several conditions.

Manuel Mota-Castillo MD
Orlando, FL

Dr. Malone responds

It is hard to assess Dr. Mota-Castillo’s case based on the information he provided. Still, one would not refute any psychiatric syndrome by citing a single case.

Most psychiatric disorders are syndromes and affect heterogeneous groups. This is true for disorders that are more prevalent in adults—such as schizophrenia and mania—and for those that present in childhood and adolescence—such as conduct disorder, ODD, and ADHD. Heterogeneity within disorders is no doubt related to underlying individual differences in genetics and environment and contributes to differences in symptom expression and treatment response.

Dr. Mota-Castillo did not present symptoms listed under DSM-IV-TR, so it is unclear how the patient was diagnosed. Diagnoses:

• are one clinician’s impression or the consensus of several clinicians
• are based on one patient encounter or ongoing treatment
• occur with or without input from other sources, such as parents and school
• are made with or without validated structured interviews.

Conduct disorder and ODDare part of DSM diagnostic nomenclature,¹ and the APA and American Academy of Child and Adolescent Psychiatry recognize both disorders. Reducing aggression associated with either disorder has long been the most common reason for psychiatric consultation in children.²

Also, Dr. Mota-Castillo prescribed olanzapine and lamotrigine, apparently for simultaneous use. The main point of our case was to discourage polypharmacy—something most experts agree should be avoided³ —by carefully starting one drug before adding a second. When a child receives two drugs at once, we cannot know the effect of either.

In the 15-year-old’s case, as often happens, the prescribed treatment might not have changed the symptoms; some symptoms remit spontaneously.

Nor does drug response clarify diagnosis. For example, both bipolar disorder and aggression in conduct disorder (and in many other conditions) may respond to an antipsychotic.⁴ Lithium and other treatments for mania have been shown to reduce severe aggression in nonmanic children and adolescents with conduct disorder.^5,6

Richard P. Malone, MD
Associate professor
Eastern Pennsylvania Psychiatric Institute
Drexel University College of Medicine
Philadelphia, PA

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed-rev). Washington, DC: American Psychiatric Association, 2000.
2. Kazdin AE. Conduct disorders in childhood and adolescence, vol. 9: developmental clinical psychology and psychiatry series. Newbury Park, CA: Sage Publications, 1987.
3. Pappadopulos E, Macintyre JC II, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY): Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145–61.
4. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment.New York: Marcel Dekker, 2003:331–49.
5. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000;57(7):649–54.
6. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34(4):445–53.

I am rebutting “How to reduce aggression in patients with conduct disorder” (Current Psychiatry, April 2004).

A 15-year-old ended his first two visits with me under police custody and was committed both times. After the first commitment, his grandmother filed a petition alleging unruly/delinquent behavior, and a judge ordered the boy to take his prescribed mood stabilizers. That was necessary because the hospital psychiatrist had determined that the boy was not mentally ill and that his grandmother needed parenting classes. The youth’s original diagnosis—conduct disorder and oppositional-defiant disorder (ODD)—contradicted my diagnosis: bipolar disorder, mixed.

During the second hospitalization, a psychiatrist diagnosed the youth as having attentiondeficit/hyperactivity disorder (ADHD). The doctor prescribed methylphenidate and oxcarbazepine, but the patient’s guardian did not consent to the medications.

Facing a sentence at the county juvenile detention center, the youth started taking olanzapine, 10 mg at bedtime, and lamotrigine, 25 mg bid titrated to 50 mg bid, as I had prescribed. His grandmother says that he no longer exhibits defiant behavior. At his third visit, he shook my hand and said, “Thank you for finding the right medications for me.”

I have seen hundreds of similar cases over 10 years. To paraphrase a colleague, diagnosing somebody with conduct disorder or ODD is like diagnosing a patient with a runny nose after a thorough emergency room examination.

I applaud the American Association of Community Psychiatry’s efforts to urge the American Psychiatric Association (APA) to abolish the conduct disorder diagnosis. I also support the many researchers who are requesting elimination of conduct disorder and ODD. These are not real and specific diagnoses but are alleged syndromes that express several conditions.

Manuel Mota-Castillo MD
Orlando, FL

Dr. Malone responds

It is hard to assess Dr. Mota-Castillo’s case based on the information he provided. Still, one would not refute any psychiatric syndrome by citing a single case.

Most psychiatric disorders are syndromes and affect heterogeneous groups. This is true for disorders that are more prevalent in adults—such as schizophrenia and mania—and for those that present in childhood and adolescence—such as conduct disorder, ODD, and ADHD. Heterogeneity within disorders is no doubt related to underlying individual differences in genetics and environment and contributes to differences in symptom expression and treatment response.

Dr. Mota-Castillo did not present symptoms listed under DSM-IV-TR, so it is unclear how the patient was diagnosed. Diagnoses:

• are one clinician’s impression or the consensus of several clinicians
• are based on one patient encounter or ongoing treatment
• occur with or without input from other sources, such as parents and school
• are made with or without validated structured interviews.

Conduct disorder and ODDare part of DSM diagnostic nomenclature,¹ and the APA and American Academy of Child and Adolescent Psychiatry recognize both disorders. Reducing aggression associated with either disorder has long been the most common reason for psychiatric consultation in children.²

Also, Dr. Mota-Castillo prescribed olanzapine and lamotrigine, apparently for simultaneous use. The main point of our case was to discourage polypharmacy—something most experts agree should be avoided³ —by carefully starting one drug before adding a second. When a child receives two drugs at once, we cannot know the effect of either.

In the 15-year-old’s case, as often happens, the prescribed treatment might not have changed the symptoms; some symptoms remit spontaneously.

Nor does drug response clarify diagnosis. For example, both bipolar disorder and aggression in conduct disorder (and in many other conditions) may respond to an antipsychotic.⁴ Lithium and other treatments for mania have been shown to reduce severe aggression in nonmanic children and adolescents with conduct disorder.^5,6

Richard P. Malone, MD
Associate professor
Eastern Pennsylvania Psychiatric Institute
Drexel University College of Medicine
Philadelphia, PA

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed-rev). Washington, DC: American Psychiatric Association, 2000.
2. Kazdin AE. Conduct disorders in childhood and adolescence, vol. 9: developmental clinical psychology and psychiatry series. Newbury Park, CA: Sage Publications, 1987.
3. Pappadopulos E, Macintyre JC II, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY): Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145–61.
4. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment.New York: Marcel Dekker, 2003:331–49.
5. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000;57(7):649–54.
6. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34(4):445–53.

In our small community hospital—with limited financial and medical resources—we have designed and implemented an outpatient alcohol detoxification clinical practice guideline to provide cost-effective, evidence-based medical care to our patients, in support of their alcohol treatment.

Those patients with mild-to-moderate alcohol withdrawal symptoms and no serious psychiatric or medical comorbidities can be safely treated in the outpatient setting. Patients with history of severe withdrawal symptoms, seizures or delirium tremens, comorbid serious psychiatric or medical illnesses, or lack of reliable support network should be considered for detoxification in the inpatient setting.

The problem of alcohol withdrawal

Up to 71% of individuals presenting for alcohol detoxification manifest significant symptoms of alcohol withdrawal.⁴ Alcohol withdrawal is a clinical syndrome that affects people accustomed to regular alcohol intake who either decrease their alcohol consumption or stop drinking completely.

Physiology

Alcohol enhances gamma-aminobutyric acid’s (GABA) inhibitory effects on signal-receiving neurons, thereby lowering neuronal activity, leading to an increase in excitatory glutamate receptors. Over time, tolerance occurs as GABA receptors become less responsive to neurotransmitters, and more alcohol is required to produce the same inhibitory effect. When alcohol is removed acutely, the number of excitatory glutamate receptors remains, but without the suppressive GABA effect.⁵ This situation leads to the signs and symptoms of alcohol withdrawal.

Symptoms

Noticeable alcohol withdrawal symptoms may appear within hours of cessation or decreasing alcohol intake. The most common symptoms include tremor, craving for alcohol, insomnia, vivid dreams, anxiety, hypervigilance, agitation, irritability, loss of appetite, nausea, vomiting, headache, and sweating.⁵ Even without treatment, most of these relatively benign symptoms resolve within hours to days.

More concerning are hallucinations, delirium tremens (DTs), and seizures. Transient auditory or visual hallucinations may occur within the first 2 days of decreasing or discontinuing alcohol consumption, and can be separate from DTs. DTs, which present within 2 to 4 days of the last drink (and can last up to 3 to 4 days), are characterized by disorientation, persistent visual and auditory hallucinations, agitation and tremulousness, and autonomic signs resulting from the activation of stress-related hormones. These signs include tachycardia, hypertension, and fevers.

DTs are much more serious than the “alcohol shakes”—5% of patients who experience DTs die from metabolic complications.⁶ The occurrence of DTs is 5.3 times higher in men than in women;⁷ however, women may exhibit fewer autonomic symptoms, making DTs in women more difficult to diagnose.⁶

Grand mal seizures can occur in up to 25% of alcoholics undergoing withdrawal.⁴ If alcohol-related seizures do occur, they generally do so within 1 day of cessation of alcohol intake, but can occur up to 5 days later.

Risk factors for prolonged or complicated alcohol withdrawal include duration of alcohol consumption, the number of lifetime prior detoxifications, prior seizures, prior episodes of DTs, and current intense craving for alcohol.^6-10

Before treatment: assess and stabilize

Initial assessment of the patient

Before initiating treatment for alcohol withdrawal, perform a thorough assessment of the patient’s medical condition. This evaluation should include an assessment of coexisting medical and psychiatric conditions, the severity of previous withdrawal symptoms, and the risk factors for withdrawal complications. The initial symptoms of alcohol withdrawal are not specific and may mimic other serious disease conditions; therefore, the initial assessment should exclude potentially serious medical and psychiatric comorbidities.

Initially, assessment of common alcohol-related medical problems should be conducted. These complications include gastritis, gastrointestinal bleeding, liver disease, cardiomyopathy, pancreatitis, neurological impairment, electrolyte imbalances, and nutritional deficiencies. A physical examination should be performed to assess for arrhythmias, congestive heart failure, hepatic or pancreatic disease, infectious conditions, bleeding, and nervous system impairment.

Initial alcohol level and urine drug screen should be assessed, as recent high levels of alcohol intake and substance abuse place the patient at higher risk for complications. Unstable mood disorders—delirium, psychosis, severe depression, suicidal or homicidal ideation—while potentially difficult to assess during intoxication, need to be considered and ruled out.

Stabilize the patient

After initial assessment, vital signs (eg, heart rate, blood pressure, and temperature) should be stabilized while fluid, electrolyte, and nutritional disturbances are corrected. Some patients undergoing alcohol withdrawal may require intravenous fluids to correct severe dehydration resulting from vomiting, diarrhea, sweating, and fever.

 

Alcoholics are often deficient in electrolytes or minerals, including thiamine, folate, and magnesium (although replacing magnesium makes no difference in clinically meaningful outcomes) (level of evidence [LOE]: 1, double-blind randomized controlled trial).¹¹ All patients being treated for alcohol withdrawal should be given 100 mg of thiamine immediately and daily (LOE: 3; insufficient evidence from randomized controlled trials to guide clinicians in the dose, frequency, route, or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse).⁴ Thiamine should be given before glucose containing fluids, to avoid the risk of precipitating Wernicke syndrome (LOE: 3).¹²

Assess the severity of the withdrawal

Once a diagnosis of alcohol withdrawal is made, complete an assessment of the severity of withdrawal and the risk of complications. The best validated tool is the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) symptom scale (Figure 1).¹⁰ This instrument rates 10 withdrawal features; it takes only a few minutes to administer and may be repeated when re-evaluation is necessary. CIWA-Ar scores of ≤8 are suggestive of mild withdrawal symptoms, while those ≥15 confer an increased risk for confusion and seizures.

CIWA-Ar is reliable, brief, uncomplicated, and clinically useful scale that can also be used to monitor response to treatment. It offers an increase in efficiency over the original CIWA-A scale, while retaining clinical usefulness, validity, and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal (strength of recommendation [SOR]=A].^5,13

Pharmacotherapy

Patients experiencing more serious withdrawal (with CIWA-Ar scores >8) should receive pharmacotherapy to treat their symptoms and reduce their risk of seizures and DTs (SOR=A).¹⁴

Benzodiazepines

Benzodiazepines are the mainstay of treatment in alcohol withdrawal (number needed to treat [NNT]=17; data from large meta-analysis of 6 prospective, placebo-controlled trials) (SOR=A).^10,14,16 Like alcohol, these agents magnify GABA’s effect on the brain. Benzodiazepines are cross-tolerant with alcohol; during withdrawal from 1 agent, the other may serve as a substitute. Benzodiazepines also reduce the incidence of DTs and seizures (Table 1).^5,14

The most commonly used benzodiazepines are diazepam (Valium), chlordiazepoxide (Librium), and lorazepam (Ativan). All appear to be equally efficacious in treating alcohol withdrawal symptoms (LOE: 1; randomized controlled trial).

Longer-acting agents, such as chlordiazepoxide or diazepam, contribute to an overall smoother withdrawal course with lessened breakthrough or rebound symptoms, but they may also lead to excess sedation for patients with hepatic dysfunction.^17-20 Shorter-acting benzodiazepines, such as oxazepam (Serax), may result in greater discomfort and more discharges against medical advice, because alcohol withdrawal symptoms tend to recur when serum benzodiazepine levels drop.

TABLE 1
Pharmacologic treatment of alcohol withdrawal

Medication	Comments	LOE
Benzodiazepines	Remain drug of choice for acute alcohol withdrawal14	A
	Highly significant decrease in seizures and delirium
	Risk reduction 7.72 seizures/100 patients, 4.9 DTs/100 patients20
	Some abuse potential
Carbamazepine	Well-documented anticonvulsant activity; prevents seizures from alcohol Withdrawal	A
	No abuse potential
	Especially good for those with multiple previously treated withdrawals22
	Relative risk of first drink after withdrawal in benzodiazepine group over 3 times higher than carbamazepine22
	If carbamazepine-treated patients relapse, they drink less than benzodiazepine-treated patients [absolute risk reduction=4]22
Valproic acid	Significantly affects the course of acute alcohol withdrawal and reduces need for treatment with a benzodiazepine [absolute risk reduction=4]24	A
	Use limited by side effects which mimic alcohol withdrawal
	Wide therapeutic range makes unintentional overdose uncommon

 

FIGURE 2
Guiding a patient through alcohol detoxification

Anticonvulsants

Attractive alternatives to benzodiazepines include the anticonvulsants carbamazepine (Tegretol) and valproic acid (Depakote).

Carbamazepine. Carbamazepine has been used successfully for many years in Europe,²¹ but has not been used widely in the US due to the safety, efficacy, and familiarity of benzodiazepines (Table 1). The use of anticonvulsants, however, has several advantages. They are not as sedating as benzodiazepines and do not have the abuse potential, making them particularly useful in the outpatient setting.

The use of anticonvulsant medication decreases the possibility of seizures, one of the more serious complications of alcohol withdrawal (NNT=36) (LOE: 1, 2 double-blind randomized controlled trials). The brain cell kindling-like phenomenon—in which repeated episodes of alcohol withdrawal is associated with increasing severity of withdrawal—is decreased with the anticonvulsant carbamazepine.¹⁴

In a double-blind controlled trial comparing carbamazepine with oxazepam, carbamazepine was shown to be superior in ameliorating global psychological distress and reducing aggression and anxiety.²¹ Stuppaeck et al showed that for alcohol withdrawal longer than 5 days, carbamazepine was statistically superior (P<.05) to oxazepam in reduction of CIWA scores.^22,23 Carbamazepine is also superior to benzodiazepines in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially in those with a history of multiple repeated withdrawals (SOR=A).²² It has been shown that patients treated with carbamazepine were less likely to have a first drink following detoxification, and if they did drink, they drank less. This difference was especially evident for those patients with a history of multiple withdrawal attempts.²²

A limitation of carbamazepine use, however, is its interaction with multiple medications that undergo hepatic oxidative metabolism, making it less useful in older patients or those with multiple medical problems. In summary, in generally healthy individuals with mild-to-moderate alcohol withdrawal, carbamazepine is just as efficacious as benzodiazepines, but has many advantages making it the drug of choice for properly selected patients (SOR=A).^21-23

Valproic acid. Another widely used anticonvulsant, valproic acid, significantly affects the course of alcohol withdrawal and reduces the need for treatment with a benzodiazepine (LOE: 1).²⁴ Two double-blind, randomized studies showed that patients treated with valproic acid for 4 to 7 days had fewer seizures, dropped out less frequently, had less severe withdrawal symptoms, and require less oxazepam than those treated with placebo or carbamazepine.^24,25

Although effective, valproic acid use may be limited by side effects—somnolence, gastrointestinal disturbances, confusion, and tremor—that mimic the symptoms of alcohol withdrawal, making it difficult to assess improvement.

Other types of medications

Alpha-adrenergic agonists,^24,30, beta-blockers,^31,33 and calcium channel blockers^34,35 have been used to control symptoms of acute alcohol withdrawal, but have demonstrated little efficacy in prevention of seizures or DTs (LOE: 1).^5,36

Treatment regimens

The acceptable medication regimens for treating alcohol withdrawal are the gradually tapering dose approach, the fixed-schedule approach, and the symptom-triggered approach. The first 2 regimens are appropriate for the pharmacological treatment of outpatient alcohol detoxification.

Gradually tapering regimen. With the gradual-dosing plan, patients receive medication according to a predetermined dosing schedule for several days as the medication is gradually discontinued (Table 2).

Fixed-schedule regimen. In the fixed-schedule dosing regimen, the patient receives a fixed dose of medication every 6 hours for 2 to 3 days regardless of severity of symptoms.

Symptom-triggered regimen. For the symptom-triggered approach, the patient’s CIWA-Ar score is determined hourly or bihourly and the medication is administered only when the score is elevated. Typically, benzodiazepines are used in a symptom-triggered regimen, although either benzodiazepines or anticonvulsants may be used in a fixed-schedule plan.

The main advantage to the symptom-triggered approach is that much less medication is used to achieve the same withdrawal state (LOE: 1).^37-39 The symptom-triggered approach has also shown a possible decrease in DTs and may lead to less oversedation.^38,39

We favor a symptom-based approach whenever adequate periodic assessment of CIWA-Ar can be performed, such as in an inpatient setting. For those patients who require pharmacological treatment during outpatient detoxification (CIWA-Ar score 8–15), we prefer the gradually tapering or fixed dosing plan, to provide a margin of safety, simplify the dosing schedule, and maximize compliance (SOR: C, expert opinion).¹⁴

TABLE 2
Outpatient treatment for alcohol detoxification

Thiamine – 100 mg orally per day (for 5 days)
Consider folate (1 mg) and multiple vitamin injection
One of the following regimens:
3-day supply (only) of the following: Chlordiazepoxide
50–100 mg every 6 hours for 4 doses, then
25–50 mg every 6 hours for 8 doses
Diazepam
10–20 mg every 6 hours for 4 doses, then
5–10 mg every 6 hours for 8 doses
Lorazepam
2–4 mg every 6 hours for 4 doses, then
1–2 mg every 6 hours for 8 doses (consider this choice if significant hepatic dysfunction)
Carbamazepine (Tegretol) —5-day supply
200 mg 4 times on day 1,
200 mg 3 times on day 2,
200 mg 2 times on day 3,
200 mg daily for 2 more days (5 days total)

 

Inpatient vs outpatient treatment

Most patients undergoing alcohol withdrawal may be treated safely in either an inpatient or out-patient setting (SOR=A).⁴⁰ Treatment professionals should assess whether inpatient or outpatient treatment would contribute more therapeutically to an alcoholic’s recovery process.⁴¹

Patients with severe alcohol withdrawal symptoms (CIWA-Ar ≥15), previous history of DTs or seizures, or those with serious psychiatric or medical comorbidities should be considered for detoxification in an inpatient setting (SOR=B) (Table 3).^10,42 The main advantage of inpatient detoxification is the availability of constant medical care, supervision, and treatment of serious complications.

A major disadvantage is the high cost of inpatient treatment. Hayashida and colleagues found inpatient treatment to be significantly more costly than outpatient treatment ($3,319–$3,665 vs $175–$388).⁴³ Additionally, while inpatient care may temporarily relieve people from the social stressors that contribute to their alcohol problem, repeated inpatient detoxification may not provide an overall therapeutic benefit.

Most alcohol treatment programs find that <10% of patients need admission to an inpatient unit for treatment of withdrawal symptoms.⁴⁴ For patients with mild-to-moderate alcohol withdrawal symptoms (CIWA-Ar <15), and no serious psychiatric or medical comorbidities, outpatient detoxification has been shown to be as safe and effective as inpatient detoxification (SOR=A).⁴⁰ Additionally, most patients in an outpatient setting experience greater social support, and maintain the freedom to continue working or maintaining day-to-day activities with fewer disruptions, and incur fewer treatment costs.⁴¹ When assessing a patient for suitability for outpatient detoxification, it is important to ascertain motivation to stay sober, ability to return for daily nursing checks, and presence of a supportive observer at home.

TABLE 3
Criteria for inpatient alcohol detoxification

Consider transfer for inpatient detoxification if the patient:

Has current symptoms of moderate to severe alcohol withdrawal (CIWA 15) Has a known history of delirium tremens (DTs) or alcohol withdrawal seizure Needs and is unable to tolerate oral medication Is in imminent risk of harm to self or others Has had recurrent unsuccessful attempts Has had multiple past detoxifications Has a reasonable likelihood that he will not complete the ambulatory detoxification Has active psychosis or severe cognitive impairment Has concomitant medical or psychological illness Has recent high levels of alcohol consumption Has lack or reliable support network Is pregnant

Corresponding author
Chad Asplund, MD, 5663 Marshall Road, Fort Belvoir, VA 22060. E-mail: [email protected].

In our small community hospital—with limited financial and medical resources—we have designed and implemented an outpatient alcohol detoxification clinical practice guideline to provide cost-effective, evidence-based medical care to our patients, in support of their alcohol treatment.

Those patients with mild-to-moderate alcohol withdrawal symptoms and no serious psychiatric or medical comorbidities can be safely treated in the outpatient setting. Patients with history of severe withdrawal symptoms, seizures or delirium tremens, comorbid serious psychiatric or medical illnesses, or lack of reliable support network should be considered for detoxification in the inpatient setting.

The problem of alcohol withdrawal

Up to 71% of individuals presenting for alcohol detoxification manifest significant symptoms of alcohol withdrawal.⁴ Alcohol withdrawal is a clinical syndrome that affects people accustomed to regular alcohol intake who either decrease their alcohol consumption or stop drinking completely.

Physiology

Alcohol enhances gamma-aminobutyric acid’s (GABA) inhibitory effects on signal-receiving neurons, thereby lowering neuronal activity, leading to an increase in excitatory glutamate receptors. Over time, tolerance occurs as GABA receptors become less responsive to neurotransmitters, and more alcohol is required to produce the same inhibitory effect. When alcohol is removed acutely, the number of excitatory glutamate receptors remains, but without the suppressive GABA effect.⁵ This situation leads to the signs and symptoms of alcohol withdrawal.

Symptoms

Noticeable alcohol withdrawal symptoms may appear within hours of cessation or decreasing alcohol intake. The most common symptoms include tremor, craving for alcohol, insomnia, vivid dreams, anxiety, hypervigilance, agitation, irritability, loss of appetite, nausea, vomiting, headache, and sweating.⁵ Even without treatment, most of these relatively benign symptoms resolve within hours to days.

More concerning are hallucinations, delirium tremens (DTs), and seizures. Transient auditory or visual hallucinations may occur within the first 2 days of decreasing or discontinuing alcohol consumption, and can be separate from DTs. DTs, which present within 2 to 4 days of the last drink (and can last up to 3 to 4 days), are characterized by disorientation, persistent visual and auditory hallucinations, agitation and tremulousness, and autonomic signs resulting from the activation of stress-related hormones. These signs include tachycardia, hypertension, and fevers.

DTs are much more serious than the “alcohol shakes”—5% of patients who experience DTs die from metabolic complications.⁶ The occurrence of DTs is 5.3 times higher in men than in women;⁷ however, women may exhibit fewer autonomic symptoms, making DTs in women more difficult to diagnose.⁶

Grand mal seizures can occur in up to 25% of alcoholics undergoing withdrawal.⁴ If alcohol-related seizures do occur, they generally do so within 1 day of cessation of alcohol intake, but can occur up to 5 days later.

Risk factors for prolonged or complicated alcohol withdrawal include duration of alcohol consumption, the number of lifetime prior detoxifications, prior seizures, prior episodes of DTs, and current intense craving for alcohol.^6-10

Before treatment: assess and stabilize

Initial assessment of the patient

Before initiating treatment for alcohol withdrawal, perform a thorough assessment of the patient’s medical condition. This evaluation should include an assessment of coexisting medical and psychiatric conditions, the severity of previous withdrawal symptoms, and the risk factors for withdrawal complications. The initial symptoms of alcohol withdrawal are not specific and may mimic other serious disease conditions; therefore, the initial assessment should exclude potentially serious medical and psychiatric comorbidities.

Initially, assessment of common alcohol-related medical problems should be conducted. These complications include gastritis, gastrointestinal bleeding, liver disease, cardiomyopathy, pancreatitis, neurological impairment, electrolyte imbalances, and nutritional deficiencies. A physical examination should be performed to assess for arrhythmias, congestive heart failure, hepatic or pancreatic disease, infectious conditions, bleeding, and nervous system impairment.

Initial alcohol level and urine drug screen should be assessed, as recent high levels of alcohol intake and substance abuse place the patient at higher risk for complications. Unstable mood disorders—delirium, psychosis, severe depression, suicidal or homicidal ideation—while potentially difficult to assess during intoxication, need to be considered and ruled out.

Stabilize the patient

After initial assessment, vital signs (eg, heart rate, blood pressure, and temperature) should be stabilized while fluid, electrolyte, and nutritional disturbances are corrected. Some patients undergoing alcohol withdrawal may require intravenous fluids to correct severe dehydration resulting from vomiting, diarrhea, sweating, and fever.

 

Alcoholics are often deficient in electrolytes or minerals, including thiamine, folate, and magnesium (although replacing magnesium makes no difference in clinically meaningful outcomes) (level of evidence [LOE]: 1, double-blind randomized controlled trial).¹¹ All patients being treated for alcohol withdrawal should be given 100 mg of thiamine immediately and daily (LOE: 3; insufficient evidence from randomized controlled trials to guide clinicians in the dose, frequency, route, or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse).⁴ Thiamine should be given before glucose containing fluids, to avoid the risk of precipitating Wernicke syndrome (LOE: 3).¹²

Assess the severity of the withdrawal

Once a diagnosis of alcohol withdrawal is made, complete an assessment of the severity of withdrawal and the risk of complications. The best validated tool is the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) symptom scale (Figure 1).¹⁰ This instrument rates 10 withdrawal features; it takes only a few minutes to administer and may be repeated when re-evaluation is necessary. CIWA-Ar scores of ≤8 are suggestive of mild withdrawal symptoms, while those ≥15 confer an increased risk for confusion and seizures.

CIWA-Ar is reliable, brief, uncomplicated, and clinically useful scale that can also be used to monitor response to treatment. It offers an increase in efficiency over the original CIWA-A scale, while retaining clinical usefulness, validity, and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal (strength of recommendation [SOR]=A].^5,13

Pharmacotherapy

Patients experiencing more serious withdrawal (with CIWA-Ar scores >8) should receive pharmacotherapy to treat their symptoms and reduce their risk of seizures and DTs (SOR=A).¹⁴

Benzodiazepines

Benzodiazepines are the mainstay of treatment in alcohol withdrawal (number needed to treat [NNT]=17; data from large meta-analysis of 6 prospective, placebo-controlled trials) (SOR=A).^10,14,16 Like alcohol, these agents magnify GABA’s effect on the brain. Benzodiazepines are cross-tolerant with alcohol; during withdrawal from 1 agent, the other may serve as a substitute. Benzodiazepines also reduce the incidence of DTs and seizures (Table 1).^5,14

The most commonly used benzodiazepines are diazepam (Valium), chlordiazepoxide (Librium), and lorazepam (Ativan). All appear to be equally efficacious in treating alcohol withdrawal symptoms (LOE: 1; randomized controlled trial).

Longer-acting agents, such as chlordiazepoxide or diazepam, contribute to an overall smoother withdrawal course with lessened breakthrough or rebound symptoms, but they may also lead to excess sedation for patients with hepatic dysfunction.^17-20 Shorter-acting benzodiazepines, such as oxazepam (Serax), may result in greater discomfort and more discharges against medical advice, because alcohol withdrawal symptoms tend to recur when serum benzodiazepine levels drop.

TABLE 1
Pharmacologic treatment of alcohol withdrawal

Medication	Comments	LOE
Benzodiazepines	Remain drug of choice for acute alcohol withdrawal14	A
	Highly significant decrease in seizures and delirium
	Risk reduction 7.72 seizures/100 patients, 4.9 DTs/100 patients20
	Some abuse potential
Carbamazepine	Well-documented anticonvulsant activity; prevents seizures from alcohol Withdrawal	A
	No abuse potential
	Especially good for those with multiple previously treated withdrawals22
	Relative risk of first drink after withdrawal in benzodiazepine group over 3 times higher than carbamazepine22
	If carbamazepine-treated patients relapse, they drink less than benzodiazepine-treated patients [absolute risk reduction=4]22
Valproic acid	Significantly affects the course of acute alcohol withdrawal and reduces need for treatment with a benzodiazepine [absolute risk reduction=4]24	A
	Use limited by side effects which mimic alcohol withdrawal
	Wide therapeutic range makes unintentional overdose uncommon

 

FIGURE 2
Guiding a patient through alcohol detoxification

Anticonvulsants

Attractive alternatives to benzodiazepines include the anticonvulsants carbamazepine (Tegretol) and valproic acid (Depakote).

Carbamazepine. Carbamazepine has been used successfully for many years in Europe,²¹ but has not been used widely in the US due to the safety, efficacy, and familiarity of benzodiazepines (Table 1). The use of anticonvulsants, however, has several advantages. They are not as sedating as benzodiazepines and do not have the abuse potential, making them particularly useful in the outpatient setting.

The use of anticonvulsant medication decreases the possibility of seizures, one of the more serious complications of alcohol withdrawal (NNT=36) (LOE: 1, 2 double-blind randomized controlled trials). The brain cell kindling-like phenomenon—in which repeated episodes of alcohol withdrawal is associated with increasing severity of withdrawal—is decreased with the anticonvulsant carbamazepine.¹⁴

In a double-blind controlled trial comparing carbamazepine with oxazepam, carbamazepine was shown to be superior in ameliorating global psychological distress and reducing aggression and anxiety.²¹ Stuppaeck et al showed that for alcohol withdrawal longer than 5 days, carbamazepine was statistically superior (P<.05) to oxazepam in reduction of CIWA scores.^22,23 Carbamazepine is also superior to benzodiazepines in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially in those with a history of multiple repeated withdrawals (SOR=A).²² It has been shown that patients treated with carbamazepine were less likely to have a first drink following detoxification, and if they did drink, they drank less. This difference was especially evident for those patients with a history of multiple withdrawal attempts.²²

A limitation of carbamazepine use, however, is its interaction with multiple medications that undergo hepatic oxidative metabolism, making it less useful in older patients or those with multiple medical problems. In summary, in generally healthy individuals with mild-to-moderate alcohol withdrawal, carbamazepine is just as efficacious as benzodiazepines, but has many advantages making it the drug of choice for properly selected patients (SOR=A).^21-23

Valproic acid. Another widely used anticonvulsant, valproic acid, significantly affects the course of alcohol withdrawal and reduces the need for treatment with a benzodiazepine (LOE: 1).²⁴ Two double-blind, randomized studies showed that patients treated with valproic acid for 4 to 7 days had fewer seizures, dropped out less frequently, had less severe withdrawal symptoms, and require less oxazepam than those treated with placebo or carbamazepine.^24,25

Although effective, valproic acid use may be limited by side effects—somnolence, gastrointestinal disturbances, confusion, and tremor—that mimic the symptoms of alcohol withdrawal, making it difficult to assess improvement.

Other types of medications

Alpha-adrenergic agonists,^24,30, beta-blockers,^31,33 and calcium channel blockers^34,35 have been used to control symptoms of acute alcohol withdrawal, but have demonstrated little efficacy in prevention of seizures or DTs (LOE: 1).^5,36

Treatment regimens

The acceptable medication regimens for treating alcohol withdrawal are the gradually tapering dose approach, the fixed-schedule approach, and the symptom-triggered approach. The first 2 regimens are appropriate for the pharmacological treatment of outpatient alcohol detoxification.

Gradually tapering regimen. With the gradual-dosing plan, patients receive medication according to a predetermined dosing schedule for several days as the medication is gradually discontinued (Table 2).

Fixed-schedule regimen. In the fixed-schedule dosing regimen, the patient receives a fixed dose of medication every 6 hours for 2 to 3 days regardless of severity of symptoms.

Symptom-triggered regimen. For the symptom-triggered approach, the patient’s CIWA-Ar score is determined hourly or bihourly and the medication is administered only when the score is elevated. Typically, benzodiazepines are used in a symptom-triggered regimen, although either benzodiazepines or anticonvulsants may be used in a fixed-schedule plan.

The main advantage to the symptom-triggered approach is that much less medication is used to achieve the same withdrawal state (LOE: 1).^37-39 The symptom-triggered approach has also shown a possible decrease in DTs and may lead to less oversedation.^38,39

We favor a symptom-based approach whenever adequate periodic assessment of CIWA-Ar can be performed, such as in an inpatient setting. For those patients who require pharmacological treatment during outpatient detoxification (CIWA-Ar score 8–15), we prefer the gradually tapering or fixed dosing plan, to provide a margin of safety, simplify the dosing schedule, and maximize compliance (SOR: C, expert opinion).¹⁴

TABLE 2
Outpatient treatment for alcohol detoxification

Thiamine – 100 mg orally per day (for 5 days)
Consider folate (1 mg) and multiple vitamin injection
One of the following regimens:
3-day supply (only) of the following: Chlordiazepoxide
50–100 mg every 6 hours for 4 doses, then
25–50 mg every 6 hours for 8 doses
Diazepam
10–20 mg every 6 hours for 4 doses, then
5–10 mg every 6 hours for 8 doses
Lorazepam
2–4 mg every 6 hours for 4 doses, then
1–2 mg every 6 hours for 8 doses (consider this choice if significant hepatic dysfunction)
Carbamazepine (Tegretol) —5-day supply
200 mg 4 times on day 1,
200 mg 3 times on day 2,
200 mg 2 times on day 3,
200 mg daily for 2 more days (5 days total)

 

Inpatient vs outpatient treatment

Most patients undergoing alcohol withdrawal may be treated safely in either an inpatient or out-patient setting (SOR=A).⁴⁰ Treatment professionals should assess whether inpatient or outpatient treatment would contribute more therapeutically to an alcoholic’s recovery process.⁴¹

Patients with severe alcohol withdrawal symptoms (CIWA-Ar ≥15), previous history of DTs or seizures, or those with serious psychiatric or medical comorbidities should be considered for detoxification in an inpatient setting (SOR=B) (Table 3).^10,42 The main advantage of inpatient detoxification is the availability of constant medical care, supervision, and treatment of serious complications.

A major disadvantage is the high cost of inpatient treatment. Hayashida and colleagues found inpatient treatment to be significantly more costly than outpatient treatment ($3,319–$3,665 vs $175–$388).⁴³ Additionally, while inpatient care may temporarily relieve people from the social stressors that contribute to their alcohol problem, repeated inpatient detoxification may not provide an overall therapeutic benefit.

Most alcohol treatment programs find that <10% of patients need admission to an inpatient unit for treatment of withdrawal symptoms.⁴⁴ For patients with mild-to-moderate alcohol withdrawal symptoms (CIWA-Ar <15), and no serious psychiatric or medical comorbidities, outpatient detoxification has been shown to be as safe and effective as inpatient detoxification (SOR=A).⁴⁰ Additionally, most patients in an outpatient setting experience greater social support, and maintain the freedom to continue working or maintaining day-to-day activities with fewer disruptions, and incur fewer treatment costs.⁴¹ When assessing a patient for suitability for outpatient detoxification, it is important to ascertain motivation to stay sober, ability to return for daily nursing checks, and presence of a supportive observer at home.

TABLE 3
Criteria for inpatient alcohol detoxification

Consider transfer for inpatient detoxification if the patient:

Has current symptoms of moderate to severe alcohol withdrawal (CIWA 15) Has a known history of delirium tremens (DTs) or alcohol withdrawal seizure Needs and is unable to tolerate oral medication Is in imminent risk of harm to self or others Has had recurrent unsuccessful attempts Has had multiple past detoxifications Has a reasonable likelihood that he will not complete the ambulatory detoxification Has active psychosis or severe cognitive impairment Has concomitant medical or psychological illness Has recent high levels of alcohol consumption Has lack or reliable support network Is pregnant

Corresponding author
Chad Asplund, MD, 5663 Marshall Road, Fort Belvoir, VA 22060. E-mail: [email protected].

In our small community hospital—with limited financial and medical resources—we have designed and implemented an outpatient alcohol detoxification clinical practice guideline to provide cost-effective, evidence-based medical care to our patients, in support of their alcohol treatment.

Those patients with mild-to-moderate alcohol withdrawal symptoms and no serious psychiatric or medical comorbidities can be safely treated in the outpatient setting. Patients with history of severe withdrawal symptoms, seizures or delirium tremens, comorbid serious psychiatric or medical illnesses, or lack of reliable support network should be considered for detoxification in the inpatient setting.

The problem of alcohol withdrawal

Up to 71% of individuals presenting for alcohol detoxification manifest significant symptoms of alcohol withdrawal.⁴ Alcohol withdrawal is a clinical syndrome that affects people accustomed to regular alcohol intake who either decrease their alcohol consumption or stop drinking completely.

Physiology

Alcohol enhances gamma-aminobutyric acid’s (GABA) inhibitory effects on signal-receiving neurons, thereby lowering neuronal activity, leading to an increase in excitatory glutamate receptors. Over time, tolerance occurs as GABA receptors become less responsive to neurotransmitters, and more alcohol is required to produce the same inhibitory effect. When alcohol is removed acutely, the number of excitatory glutamate receptors remains, but without the suppressive GABA effect.⁵ This situation leads to the signs and symptoms of alcohol withdrawal.

Symptoms

Noticeable alcohol withdrawal symptoms may appear within hours of cessation or decreasing alcohol intake. The most common symptoms include tremor, craving for alcohol, insomnia, vivid dreams, anxiety, hypervigilance, agitation, irritability, loss of appetite, nausea, vomiting, headache, and sweating.⁵ Even without treatment, most of these relatively benign symptoms resolve within hours to days.

More concerning are hallucinations, delirium tremens (DTs), and seizures. Transient auditory or visual hallucinations may occur within the first 2 days of decreasing or discontinuing alcohol consumption, and can be separate from DTs. DTs, which present within 2 to 4 days of the last drink (and can last up to 3 to 4 days), are characterized by disorientation, persistent visual and auditory hallucinations, agitation and tremulousness, and autonomic signs resulting from the activation of stress-related hormones. These signs include tachycardia, hypertension, and fevers.

DTs are much more serious than the “alcohol shakes”—5% of patients who experience DTs die from metabolic complications.⁶ The occurrence of DTs is 5.3 times higher in men than in women;⁷ however, women may exhibit fewer autonomic symptoms, making DTs in women more difficult to diagnose.⁶

Grand mal seizures can occur in up to 25% of alcoholics undergoing withdrawal.⁴ If alcohol-related seizures do occur, they generally do so within 1 day of cessation of alcohol intake, but can occur up to 5 days later.

Risk factors for prolonged or complicated alcohol withdrawal include duration of alcohol consumption, the number of lifetime prior detoxifications, prior seizures, prior episodes of DTs, and current intense craving for alcohol.^6-10

Before treatment: assess and stabilize

Initial assessment of the patient

Before initiating treatment for alcohol withdrawal, perform a thorough assessment of the patient’s medical condition. This evaluation should include an assessment of coexisting medical and psychiatric conditions, the severity of previous withdrawal symptoms, and the risk factors for withdrawal complications. The initial symptoms of alcohol withdrawal are not specific and may mimic other serious disease conditions; therefore, the initial assessment should exclude potentially serious medical and psychiatric comorbidities.

Initially, assessment of common alcohol-related medical problems should be conducted. These complications include gastritis, gastrointestinal bleeding, liver disease, cardiomyopathy, pancreatitis, neurological impairment, electrolyte imbalances, and nutritional deficiencies. A physical examination should be performed to assess for arrhythmias, congestive heart failure, hepatic or pancreatic disease, infectious conditions, bleeding, and nervous system impairment.

Initial alcohol level and urine drug screen should be assessed, as recent high levels of alcohol intake and substance abuse place the patient at higher risk for complications. Unstable mood disorders—delirium, psychosis, severe depression, suicidal or homicidal ideation—while potentially difficult to assess during intoxication, need to be considered and ruled out.

Stabilize the patient

After initial assessment, vital signs (eg, heart rate, blood pressure, and temperature) should be stabilized while fluid, electrolyte, and nutritional disturbances are corrected. Some patients undergoing alcohol withdrawal may require intravenous fluids to correct severe dehydration resulting from vomiting, diarrhea, sweating, and fever.

 

Alcoholics are often deficient in electrolytes or minerals, including thiamine, folate, and magnesium (although replacing magnesium makes no difference in clinically meaningful outcomes) (level of evidence [LOE]: 1, double-blind randomized controlled trial).¹¹ All patients being treated for alcohol withdrawal should be given 100 mg of thiamine immediately and daily (LOE: 3; insufficient evidence from randomized controlled trials to guide clinicians in the dose, frequency, route, or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse).⁴ Thiamine should be given before glucose containing fluids, to avoid the risk of precipitating Wernicke syndrome (LOE: 3).¹²

Assess the severity of the withdrawal

Once a diagnosis of alcohol withdrawal is made, complete an assessment of the severity of withdrawal and the risk of complications. The best validated tool is the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) symptom scale (Figure 1).¹⁰ This instrument rates 10 withdrawal features; it takes only a few minutes to administer and may be repeated when re-evaluation is necessary. CIWA-Ar scores of ≤8 are suggestive of mild withdrawal symptoms, while those ≥15 confer an increased risk for confusion and seizures.

CIWA-Ar is reliable, brief, uncomplicated, and clinically useful scale that can also be used to monitor response to treatment. It offers an increase in efficiency over the original CIWA-A scale, while retaining clinical usefulness, validity, and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal (strength of recommendation [SOR]=A].^5,13

Pharmacotherapy

Patients experiencing more serious withdrawal (with CIWA-Ar scores >8) should receive pharmacotherapy to treat their symptoms and reduce their risk of seizures and DTs (SOR=A).¹⁴

Benzodiazepines

Benzodiazepines are the mainstay of treatment in alcohol withdrawal (number needed to treat [NNT]=17; data from large meta-analysis of 6 prospective, placebo-controlled trials) (SOR=A).^10,14,16 Like alcohol, these agents magnify GABA’s effect on the brain. Benzodiazepines are cross-tolerant with alcohol; during withdrawal from 1 agent, the other may serve as a substitute. Benzodiazepines also reduce the incidence of DTs and seizures (Table 1).^5,14

The most commonly used benzodiazepines are diazepam (Valium), chlordiazepoxide (Librium), and lorazepam (Ativan). All appear to be equally efficacious in treating alcohol withdrawal symptoms (LOE: 1; randomized controlled trial).

Longer-acting agents, such as chlordiazepoxide or diazepam, contribute to an overall smoother withdrawal course with lessened breakthrough or rebound symptoms, but they may also lead to excess sedation for patients with hepatic dysfunction.^17-20 Shorter-acting benzodiazepines, such as oxazepam (Serax), may result in greater discomfort and more discharges against medical advice, because alcohol withdrawal symptoms tend to recur when serum benzodiazepine levels drop.

TABLE 1
Pharmacologic treatment of alcohol withdrawal

Medication	Comments	LOE
Benzodiazepines	Remain drug of choice for acute alcohol withdrawal14	A
	Highly significant decrease in seizures and delirium
	Risk reduction 7.72 seizures/100 patients, 4.9 DTs/100 patients20
	Some abuse potential
Carbamazepine	Well-documented anticonvulsant activity; prevents seizures from alcohol Withdrawal	A
	No abuse potential
	Especially good for those with multiple previously treated withdrawals22
	Relative risk of first drink after withdrawal in benzodiazepine group over 3 times higher than carbamazepine22
	If carbamazepine-treated patients relapse, they drink less than benzodiazepine-treated patients [absolute risk reduction=4]22
Valproic acid	Significantly affects the course of acute alcohol withdrawal and reduces need for treatment with a benzodiazepine [absolute risk reduction=4]24	A
	Use limited by side effects which mimic alcohol withdrawal
	Wide therapeutic range makes unintentional overdose uncommon

 

FIGURE 2
Guiding a patient through alcohol detoxification

Anticonvulsants

Attractive alternatives to benzodiazepines include the anticonvulsants carbamazepine (Tegretol) and valproic acid (Depakote).

Carbamazepine. Carbamazepine has been used successfully for many years in Europe,²¹ but has not been used widely in the US due to the safety, efficacy, and familiarity of benzodiazepines (Table 1). The use of anticonvulsants, however, has several advantages. They are not as sedating as benzodiazepines and do not have the abuse potential, making them particularly useful in the outpatient setting.

The use of anticonvulsant medication decreases the possibility of seizures, one of the more serious complications of alcohol withdrawal (NNT=36) (LOE: 1, 2 double-blind randomized controlled trials). The brain cell kindling-like phenomenon—in which repeated episodes of alcohol withdrawal is associated with increasing severity of withdrawal—is decreased with the anticonvulsant carbamazepine.¹⁴

In a double-blind controlled trial comparing carbamazepine with oxazepam, carbamazepine was shown to be superior in ameliorating global psychological distress and reducing aggression and anxiety.²¹ Stuppaeck et al showed that for alcohol withdrawal longer than 5 days, carbamazepine was statistically superior (P<.05) to oxazepam in reduction of CIWA scores.^22,23 Carbamazepine is also superior to benzodiazepines in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially in those with a history of multiple repeated withdrawals (SOR=A).²² It has been shown that patients treated with carbamazepine were less likely to have a first drink following detoxification, and if they did drink, they drank less. This difference was especially evident for those patients with a history of multiple withdrawal attempts.²²

A limitation of carbamazepine use, however, is its interaction with multiple medications that undergo hepatic oxidative metabolism, making it less useful in older patients or those with multiple medical problems. In summary, in generally healthy individuals with mild-to-moderate alcohol withdrawal, carbamazepine is just as efficacious as benzodiazepines, but has many advantages making it the drug of choice for properly selected patients (SOR=A).^21-23

Valproic acid. Another widely used anticonvulsant, valproic acid, significantly affects the course of alcohol withdrawal and reduces the need for treatment with a benzodiazepine (LOE: 1).²⁴ Two double-blind, randomized studies showed that patients treated with valproic acid for 4 to 7 days had fewer seizures, dropped out less frequently, had less severe withdrawal symptoms, and require less oxazepam than those treated with placebo or carbamazepine.^24,25

Although effective, valproic acid use may be limited by side effects—somnolence, gastrointestinal disturbances, confusion, and tremor—that mimic the symptoms of alcohol withdrawal, making it difficult to assess improvement.

Other types of medications

Alpha-adrenergic agonists,^24,30, beta-blockers,^31,33 and calcium channel blockers^34,35 have been used to control symptoms of acute alcohol withdrawal, but have demonstrated little efficacy in prevention of seizures or DTs (LOE: 1).^5,36

Treatment regimens

The acceptable medication regimens for treating alcohol withdrawal are the gradually tapering dose approach, the fixed-schedule approach, and the symptom-triggered approach. The first 2 regimens are appropriate for the pharmacological treatment of outpatient alcohol detoxification.

Gradually tapering regimen. With the gradual-dosing plan, patients receive medication according to a predetermined dosing schedule for several days as the medication is gradually discontinued (Table 2).

Fixed-schedule regimen. In the fixed-schedule dosing regimen, the patient receives a fixed dose of medication every 6 hours for 2 to 3 days regardless of severity of symptoms.

Symptom-triggered regimen. For the symptom-triggered approach, the patient’s CIWA-Ar score is determined hourly or bihourly and the medication is administered only when the score is elevated. Typically, benzodiazepines are used in a symptom-triggered regimen, although either benzodiazepines or anticonvulsants may be used in a fixed-schedule plan.

The main advantage to the symptom-triggered approach is that much less medication is used to achieve the same withdrawal state (LOE: 1).^37-39 The symptom-triggered approach has also shown a possible decrease in DTs and may lead to less oversedation.^38,39

We favor a symptom-based approach whenever adequate periodic assessment of CIWA-Ar can be performed, such as in an inpatient setting. For those patients who require pharmacological treatment during outpatient detoxification (CIWA-Ar score 8–15), we prefer the gradually tapering or fixed dosing plan, to provide a margin of safety, simplify the dosing schedule, and maximize compliance (SOR: C, expert opinion).¹⁴

TABLE 2
Outpatient treatment for alcohol detoxification

Thiamine – 100 mg orally per day (for 5 days)
Consider folate (1 mg) and multiple vitamin injection
One of the following regimens:
3-day supply (only) of the following: Chlordiazepoxide
50–100 mg every 6 hours for 4 doses, then
25–50 mg every 6 hours for 8 doses
Diazepam
10–20 mg every 6 hours for 4 doses, then
5–10 mg every 6 hours for 8 doses
Lorazepam
2–4 mg every 6 hours for 4 doses, then
1–2 mg every 6 hours for 8 doses (consider this choice if significant hepatic dysfunction)
Carbamazepine (Tegretol) —5-day supply
200 mg 4 times on day 1,
200 mg 3 times on day 2,
200 mg 2 times on day 3,
200 mg daily for 2 more days (5 days total)

 

Inpatient vs outpatient treatment

Most patients undergoing alcohol withdrawal may be treated safely in either an inpatient or out-patient setting (SOR=A).⁴⁰ Treatment professionals should assess whether inpatient or outpatient treatment would contribute more therapeutically to an alcoholic’s recovery process.⁴¹

Patients with severe alcohol withdrawal symptoms (CIWA-Ar ≥15), previous history of DTs or seizures, or those with serious psychiatric or medical comorbidities should be considered for detoxification in an inpatient setting (SOR=B) (Table 3).^10,42 The main advantage of inpatient detoxification is the availability of constant medical care, supervision, and treatment of serious complications.

A major disadvantage is the high cost of inpatient treatment. Hayashida and colleagues found inpatient treatment to be significantly more costly than outpatient treatment ($3,319–$3,665 vs $175–$388).⁴³ Additionally, while inpatient care may temporarily relieve people from the social stressors that contribute to their alcohol problem, repeated inpatient detoxification may not provide an overall therapeutic benefit.

Most alcohol treatment programs find that <10% of patients need admission to an inpatient unit for treatment of withdrawal symptoms.⁴⁴ For patients with mild-to-moderate alcohol withdrawal symptoms (CIWA-Ar <15), and no serious psychiatric or medical comorbidities, outpatient detoxification has been shown to be as safe and effective as inpatient detoxification (SOR=A).⁴⁰ Additionally, most patients in an outpatient setting experience greater social support, and maintain the freedom to continue working or maintaining day-to-day activities with fewer disruptions, and incur fewer treatment costs.⁴¹ When assessing a patient for suitability for outpatient detoxification, it is important to ascertain motivation to stay sober, ability to return for daily nursing checks, and presence of a supportive observer at home.

TABLE 3
Criteria for inpatient alcohol detoxification

Consider transfer for inpatient detoxification if the patient:

Has current symptoms of moderate to severe alcohol withdrawal (CIWA 15) Has a known history of delirium tremens (DTs) or alcohol withdrawal seizure Needs and is unable to tolerate oral medication Is in imminent risk of harm to self or others Has had recurrent unsuccessful attempts Has had multiple past detoxifications Has a reasonable likelihood that he will not complete the ambulatory detoxification Has active psychosis or severe cognitive impairment Has concomitant medical or psychological illness Has recent high levels of alcohol consumption Has lack or reliable support network Is pregnant

Corresponding author
Chad Asplund, MD, 5663 Marshall Road, Fort Belvoir, VA 22060. E-mail: [email protected].

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

To set limits and expectations, the therapist introduces structure such as designating work and break areas and using visual schedules and timers to indicate activity duration. Minimizing distractions and understanding the child’s sensory needs may increase motivation and attention. Initially, the therapist allows numerous breaks and then may slowly decrease them as the child progresses. Tailoring work and play materials to the child’s interests can also help increase attention.

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

 

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

Medication	Type of report	Dosage (mg/d); duration	Outcome	Adverse effects
Dextroamphetamine	Placebo-controlled10 (N=16) Case report11 (N=2)	Mean 4.8; N/A Mean 7.5; N/A	Clinical worsening Improved hyperactivity,inattention,impulsivity	Hyperactivity, irritability, decreased appetite, worsened stereotypy N/A
Levoamphetamine	Double-blind12 (N=12)	Mean 13.4	Clinical worsening	Stereotypy emerged or worsened
Methylphenidate	Retrospective13 (N=15) Open-label14 (N=9) Case report15 (N=1) Double-blind, placebo-controlled, crossover16 (N=10) Double-blind, placebo-controlled, crossover17 (N=13)	5 to 10; 26 weeks 10 to 50; 2 weeks 20; 4 weeks 20 mg/d for 2 weeks, 40 mg/d for 2 weeks 0.3 mg/kg and 0.6 mg/kg	Improved hyperactivity, impulsivity Improved hyperactivity Improved hyperactivity, concentration Modest benefit over placebo Improved hyperactivity, inattention	Irritability, insomnia, anorexia Initial mild insomnia Dysphoria, angry outbursts Statistically similar to placebo Social withdrawal, irritability
Methylphenidate, levoamphetamine, dextroamphetamine, or pemoline	Retrospective18 (N=195)	Various dosages, durations	Patients with, Asperger’s disorder were significantly more likely to respond	Agitation, dysphoria, irritability
N/A: not available

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

 

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

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

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

To set limits and expectations, the therapist introduces structure such as designating work and break areas and using visual schedules and timers to indicate activity duration. Minimizing distractions and understanding the child’s sensory needs may increase motivation and attention. Initially, the therapist allows numerous breaks and then may slowly decrease them as the child progresses. Tailoring work and play materials to the child’s interests can also help increase attention.

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

 

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

Medication	Type of report	Dosage (mg/d); duration	Outcome	Adverse effects
Dextroamphetamine	Placebo-controlled10 (N=16) Case report11 (N=2)	Mean 4.8; N/A Mean 7.5; N/A	Clinical worsening Improved hyperactivity,inattention,impulsivity	Hyperactivity, irritability, decreased appetite, worsened stereotypy N/A
Levoamphetamine	Double-blind12 (N=12)	Mean 13.4	Clinical worsening	Stereotypy emerged or worsened
Methylphenidate	Retrospective13 (N=15) Open-label14 (N=9) Case report15 (N=1) Double-blind, placebo-controlled, crossover16 (N=10) Double-blind, placebo-controlled, crossover17 (N=13)	5 to 10; 26 weeks 10 to 50; 2 weeks 20; 4 weeks 20 mg/d for 2 weeks, 40 mg/d for 2 weeks 0.3 mg/kg and 0.6 mg/kg	Improved hyperactivity, impulsivity Improved hyperactivity Improved hyperactivity, concentration Modest benefit over placebo Improved hyperactivity, inattention	Irritability, insomnia, anorexia Initial mild insomnia Dysphoria, angry outbursts Statistically similar to placebo Social withdrawal, irritability
Methylphenidate, levoamphetamine, dextroamphetamine, or pemoline	Retrospective18 (N=195)	Various dosages, durations	Patients with, Asperger’s disorder were significantly more likely to respond	Agitation, dysphoria, irritability
N/A: not available

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

 

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

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

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).

Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

To set limits and expectations, the therapist introduces structure such as designating work and break areas and using visual schedules and timers to indicate activity duration. Minimizing distractions and understanding the child’s sensory needs may increase motivation and attention. Initially, the therapist allows numerous breaks and then may slowly decrease them as the child progresses. Tailoring work and play materials to the child’s interests can also help increase attention.

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

• Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
• In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

• In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
• An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.

 

A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

Medication	Type of report	Dosage (mg/d); duration	Outcome	Adverse effects
Dextroamphetamine	Placebo-controlled10 (N=16) Case report11 (N=2)	Mean 4.8; N/A Mean 7.5; N/A	Clinical worsening Improved hyperactivity,inattention,impulsivity	Hyperactivity, irritability, decreased appetite, worsened stereotypy N/A
Levoamphetamine	Double-blind12 (N=12)	Mean 13.4	Clinical worsening	Stereotypy emerged or worsened
Methylphenidate	Retrospective13 (N=15) Open-label14 (N=9) Case report15 (N=1) Double-blind, placebo-controlled, crossover16 (N=10) Double-blind, placebo-controlled, crossover17 (N=13)	5 to 10; 26 weeks 10 to 50; 2 weeks 20; 4 weeks 20 mg/d for 2 weeks, 40 mg/d for 2 weeks 0.3 mg/kg and 0.6 mg/kg	Improved hyperactivity, impulsivity Improved hyperactivity Improved hyperactivity, concentration Modest benefit over placebo Improved hyperactivity, inattention	Irritability, insomnia, anorexia Initial mild insomnia Dysphoria, angry outbursts Statistically similar to placebo Social withdrawal, irritability
Methylphenidate, levoamphetamine, dextroamphetamine, or pemoline	Retrospective18 (N=195)	Various dosages, durations	Patients with, Asperger’s disorder were significantly more likely to respond	Agitation, dysphoria, irritability
N/A: not available

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

• In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
• In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

• In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
• In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.

 

To help meet this need, the National Institutes of Mental Health’s Research Units on Pediatric Psychopharmacology (RUPP) autism network recently completed a large, double-blind, placebo-controlled study to investigate methylphenidate’s efficacy and tolerability in PDDs. It is anticipated that the results will help us discern whether factors such as PDD subtype, patient age, dosage, or degree of mental retardation are associated with response.

Related resources

• Autism Society of America. www.autism-society.org
• McDougle CJ. Current and emerging therapeutics of autistic disorder and related pervasive developmental disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice.New York: Oxford University Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Clomipramine • Anafranil
• Clonidine • Catapres
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Guanfacine • Tenex
• Haloperidol • Haldol
• Levoamphetamine • Adderall
• Levodopa • Dopar, Laradopa
• Methylphenidate • Ritalin
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Risperidone • Risperdal

Disclosure

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

Dr. Posey receives research support from Janssen Pharmaceutica and Eli Lilly and Co. and is a speaker for Janssen Pharmaceutica.

Dr. McDougle receives research support from Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., and Bristol-Myers Squibb Co. He is a consultant to or speaker for Janssen Pharmaceutica, Pfizer Inc., Eli Lilly and Co., RepliGen Corp., and Bristol-Myers Squibb Co.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr. Posey), a Research Units on Pediatric Psychopharmacology Grant (U10MH66766-02) from the National Institute of Mental Health (NIMH) to Indiana University (Dr. McDougle, Dr. Stigler, and Dr. Posey), a Research Career Development Award (K23-MH068627-01) from the NIMH (Dr. Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development (HUD) grant (B-01-SP-IN-0200) (Dr. McDougle).