Kimberly A. Stigler, MD

Psychotropics^1,2 are used to manage maladaptive and interfering behaviors in 70% of patients with fragile X syndrome (FXS), the leading cause of hereditary mental retardation. Treatment tends to follow a developmental course:

• In children, stimulants and alpha-2 agonists are used for attention-deficit/hyperactivity disorder (ADHD)-like symptoms.
  
• In adolescents and adults, selective serotonin reuptake inhibitors (SSRIs) are used for anxiety/repetitive phenomena and second-generation antipsychotics (SGAs) for irritability.
  

This course—which is often effective—is based primarily on anecdotal descriptions and on rationales borrowed from studies of ADHD, obsessive-compulsive disorder (OCD), and autistic disorder/related pervasive developmental disorders (PDDs).³ Disease-modifying agents to target the underlying brain dysregulation inherent in FXS (Box)^1,4-10 are being investigated. For now, psychotropics can help you manage three common FXS symptom clusters: inattention and hyperactivity, anxiety, and aggression and self-injurious behavior (SIB).

Box

Table 1

Clinical characteristics of patients with fragile X syndrome

Physical features (seen in some males)	Long, narrow face
	High, arched palate
	Narrow inter-eye distance
	Enlarged ears
	Macro-orchidism
Behavioral symptoms	Inattention
	Hyperactivity
	Anxiety
	Repetitive behaviors
	Aggression and self-injurious behaviors (increased in adolescence and adulthood)
Comorbidities	Mental retardation (mean IQ for affected males in moderate range)
	Comorbid autism (25% of affected individuals)
	Frequent seizures (10% to 20% of affected males)
	Hypersensitivity to sensory Stimuli

Inattention and hyperactivity

Mike, age 6, has fragile X syndrome. He has been attending first grade for 4 months, and his teacher reports he does not sit still, runs throughout the classroom, and cannot focus on class work. Mike’s hyperactivity has been evident for 2 years but did not cause problems until first grade, his parents report.

Psychostimulants are the most frequently prescribed agents for inattention and hyperactivity in FXS, particularly in boys and male adolescents.¹ Among FXS patients prescribed ≥ 1 psychotropic, approximately 70% are taking a stimulant.^1,2

Efficacy. A clinical chart review found a 75% response rate in FXS children and adolescents who were given a stimulant for inattention and/or hyperactivity.¹ This is higher than the 25% to 49% stimulant response rate reported in patients with PDDs.^11,12

A 3-week, placebo-controlled, crossover trial of methylphenidate and dextroamphetamine noted a statistically significant response only to methylphenidate, with a positive response reported in 10 of 15 children (67%).¹³

Side effects. To date, limited information has described the rate of intolerable side effects associated with stimulant use in FXS,¹⁴ but in patients with PDD:

• 154 of 268 (57.5%) patient trials in a retrospective naturalistic study showed significant adverse effects with stimulant use.¹¹
  
• 13 of 72 (18%) subjects in a controlled trial discontinued methylphenidate because of adverse events (most commonly irritability).¹²
  

Based on these observations, possible side effects that deserve close monitoring include mood lability, exacerbation of anxiety, increased social withdrawal, irritability, insomnia, decreased appetite, and increased repetitive movements.

Antiadrenergics. The alpha-2 agonists clonidine and guanfacine are the second most-used class of agents for inattention and hyperactivity in FXS. As with stimulants, boys and male adolescents are most likely to receive alpha-2 agonists, with administration rates of 10% to 20%.^1,2

Efficacy. In one survey, nearly two-thirds (63%) of parents described clonidine as “very beneficial” to 35 children (mean age 6.6) with FXS.¹⁵ This is similar to a 70% response rate described for these alpha-2 agonists in a chart review.¹ These rates are much higher than the 24% response rate reported with guanfacine in a retrospective chart review of 80 children and adolescents with a PDD.¹⁶ In that review, guanfacine use was associated with reduced hyperactivity, insomnia, and tics, and increased attention.¹⁵

Side effects associated with alpha-2 agonists include lowered blood pressure and sedation.

 

L-acetylcarnitine—a carnitine derivative required for neuronal use and transport of fatty acids—is being investigated to treat hyperactivity in FXS. Hyperactive symptoms improved significantly with L-acetylcarnitine, as measured by the Conners’ Abbreviated Parent-Teacher Questionnaire, in a 1-year, placebo-controlled trial of 20 boys (mean age 9.2) with FXS.¹⁷

Discussion. Supporting evidence is limited, but clinicians are treating ADHD-like symptoms with stimulants and alpha-2 agonists in many FXS patients. Preliminary data indicate that stimulants may be more effective and better tolerated in individuals with FXS than in those with PDD.

Trying a stimulant or alpha-2 agonist for inattention or hyperactivity symptoms in a child or adolescent with FXS appears clinically appropriate, given the available evidence. Additional data based on placebo-controlled and standardized measures of treatment response are needed to help guide treatment.

We start Mike on methylphenidate, 5 mg in the morning, for inattention and hyperactivity. He tolerates this well, and after 2 weeks we increase the dosage to 5 mg bid. Several weeks into treatment, his teacher comments that he is beginning to stay in his seat and attends to some assigned tasks in the classroom.

Mike continued to tolerate methylphenidate over the next 4 years. We gradually increased the dosage as he grew and when he periodically developed breakthrough interfering symptoms in the classroom.

Anxiety symptoms

In grade school, Mike became increasingly nervous around schoolmates, teachers, and friends. His teachers commented that he repeated phrases when he appeared anxious. Other children in his special education class began to shun him; they found his perseveration odd and sometimes threatening.

Now that Mike is age 10 and in fifth grade, his parents decide that his anxiety, particularly in social settings, is interfering with his life.

Anxiety symptoms—including generalized nervousness and OCD-like obsessions and perseverations—are common psychotropic targets in FXS. Boys may be the FXS patients most often prescribed drugs for inattention and hyperactivity, but they are the least likely to receive antidepressants for anxiety symptoms.^1,2

Efficacy. More than 50% of female patients and men with FXS are prescribed SSRIs for anxiety (Table 2), and the reported response rate of 50% to 60%¹ is similar to that seen with SSRIs in autism and related disorders.¹⁸ In autism, a developmental approach is warranted, as SSRIs tend to be less effective and cause more side effects in children and adolescents than in adults.¹⁸

Adverse effects reported with SSRIs in FXS include behavioral activation, appetite changes, insomnia, and nausea.¹ In a study of fluoxetine for FXS symptoms, 10 of 35 patients (29%) had persistent side effects, most commonly weight loss and weight gain.¹⁹ One patient with pre-existing suicidal ideation worsened.

Watch for emergence or worsening of suicidal thoughts in all children and adolescents receiving antidepressants, whatever their target symptoms.

Mike is taking methylphenidate, 15 mg bid, for comorbid ADHD, and we add fluoxetine, 10 mg/d, for anxiety. This regimen is well-tolerated, so we increase fluoxetine to 20 mg/d at his 4-week follow-up appointment. After about 8 weeks, Mike’s parents report that his anxiety-associated symptoms are less severe.

Mike still appears nervous sometimes, but he uses markedly fewer perseverative phrases. This allows him to interact more meaningfully with peers and contributes to his social development.

Table 2

Target symptoms and treatment options for fragile X syndrome

Medication class	Target symptom cluster	Evidence for use of drug class in FXS
Stimulants	Inattention, hyperactivity	One placebo-controlled trial, two large clinic surveys
Alpha-2 agonists	Inattention, hyperactivity	One parent-interview report, two large clinic surveys
SSRIs	Anxiety-related symptoms	One mailed survey, two large clinic surveys
Atypical antipsychotics	Aggression, self-injury	Two large clinic surveys, several controlled trials in PDDs
FXS: fragile X syndrome
SSRIs: selective serotonin reuptake inhibitors
PDDs: pervasive developmental disorders.

Aggression and self-injury

Mike, now age 20 and participating daily in a vocational workshop, begins yelling profanities at coworkers. At his group home, he has been hitting staff at least twice a week when redirected.

He is no longer taking stimulants, having been weaned from methylphenidate several years ago, but he continues to take fluoxetine, 40 mg/d.

Fluoxetine¹⁹ and clonidine¹⁵ can decrease irritability in FXS, but atypical antipsychotics are most commonly used for aggression and SIB.^1,2 SGAs are prescribed to 10% to 20% of FXS patients who are taking medication^1,2—particularly to men—and have produced response rates of 60% to 100% when used for aggression and SIB.¹

Risperidone. No published reports have addressed using specific SGAs in FXS. In the PDD literature, most controlled data concerns risperidone.²⁰

The largest randomized, placebo-controlled trial enrolled 101 children ages 5 to 17 with autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior. Among the 49 children taking risperidone, 0.5 to 3.5 mg/d for 8 weeks, 34 (69%) were judged as treatment responders with significantly reduced irritable behavior, compared with 6 of 52 (12%) taking placebo.²¹ Risperidone therapy was associated with average weight gain of 2.7±2.9 kg, compared with 0.8±2.2 kg with placebo.

 

Besides weight gain, other significant side effects associated with risperidone include sedation and elevated serum prolactin. These effects often are more pronounced in children and adolescents than in adults with PDDs.²⁰

Other antipsychotics. Future use of SGAs in FXS will likely mirror the pattern seen in PDDs, where clinicians are moving towards weight-neutral antipsychotics such as ziprasidone and aripiprazole. In a preliminary report, aripiprazole reduced irritability in 5 youths with PDD.²² Our group is conducting a double-blind, placebo-controlled trial of aripiprazole in autism, targeting aggression, SIB, and irritability.

Discussion. SGAs are used most often in FXS to treat aggression and SIB, based on data from studies on treating similar symptoms in PDDs. Closely monitor patients for sedation, weight gain, and lipid, glucose, and prolactin elevations when using SGAs (Table 3). Be especially vigilant when children gain weight rapidly or show hyperprolactinemia signs while taking these drugs.

After being suspended from the vocational workshop, Mike is treated at a local mental health center for aggressive behaviors. He tolerates an initial dosage of aripiprazole,2.5 mg/d, which is titrated in 2.5-mg increments biweekly to 10 mg/d. At this dosage, he stops hitting staff members and his yelling of profanities is greatly reduced. Over several months, Mike returns to his vocational workshop and maintains residence at his group home.

Table 3

Medication side effects and recommended monitoring

Medication class	Side effects	Medication monitoring
Stimulants	Anorexia, insomnia, agitation, exacerbation of tics	Observe closely when starting treatment and increasing dosage
Alpha-2 agonists	Lowered blood pressure, sedation, dizziness	Observe closely when starting treatment and increasing dosage
		Check blood pressure with all dosage changes and at all clinic visits
SSRIs	Irritability, mood lability, nausea, sleep and appetite disturbances, suicidality	Observe closely when starting treatment and increasing dosage
Atypical antipsychotics	Sedation, weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, EPS, NMS, tardive dyskinesia	Obtain metabolic profile, including fasting lipids, glucose, and prolactin levels
		Monitor for weight gain and signs of EPS
EPS: extrapyramidal symptoms
NMS: neuroleptic malignant syndrome
SSRIs: selective serotonin reuptake inhibitors

Genetic-related treatments

Studies are needed to investigate the use of stimulants, SSRIs, and antipsychotics in patients with FXS unaccompanied by generalized anxiety disorder, OCD, ADHD, or PDDs. How FXS patients without those comorbidities will respond to drug treatment is unknown. Also, little also is known about possible side effects associated with combining drug treatments in individuals with FXS.

Future drug treatment in FXS will likely focus on agents that target the underlying neurochemical dysregulation associated with the FXS genotype. This approach might reduce interfering behaviors and alter the course of cognitive dysfunction—including mental retardation—associated with FXS.

Past attempts to correct FXS’ neurochemical abnormalities focused on using folic acid. The term “fragile X” describes how the X chromosome of individuals with FXS fractures in a folate-deprived medium. Many controlled trials of folic acid in FXS did not support earlier positive reports, however.⁴

Greater understanding of fragile X mental retardation protein (FMRP) function has led to the metabotropic glutamate receptor (mGluR) theory.⁷ It holds that FMRP underproduction allows exaggerated group 1 mGluR activity and leads to the FXS neurobehavioral phenotype. Researchers now are attempting to reverse the neurochemical impact of insufficient FMRP with two medication classes:

• selective group 1 mGluR receptor antagonists (mGluR5 antagonists, in particular). The mGluR5 receptor antagonist MPEP has shown the ability to rescue normal behaviors in animal models of FXS. MPEP and lithium have reversed behaviors associated with FXS and—at the microscopic level—rescued synaptic plasticity.^23,24 In the drosophila fly model of FXS, lithium reduced activity in the mGluR cascade, thus compensating for lack of FMRP.²³
  
• positive AMPA receptor modulators (ampakines) that promote activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.⁹ Excessive mGluR activity appears to impair AMPA receptors’ ability to promote cortical development, memory, and learning.⁷ Reduced AMPA receptors have been shown in the FXS mouse model,²⁵ and an ampakine is being investigated in a study of men with FXS and autism.¹
  

Related resources

• FRAXA: The Fragile X Research Foundation. Founded by parents of children with fragile X syndrome to increase funding for research toward effective treatments. www.fraxa.org.
  
• The National Fragile X Foundation. Provides educational and emotional support for fragile X families and promotes public and professional awareness. www.fragilex.org.
  
• Hagerman RJ, Hagerman PJ, eds. Fragile X syndrome: diagnosis, treatment, and research, 3rd ed. Baltimore, MD: The Johns Hopkins University Press; 2002.
  

Drug brand names

• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Guanfacine • Tenex
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Disclosures

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

Dr. Stigler receives grant/research support from Bristol-Myers Squibb Co. and Janssen Pharmaceutica.

 

Dr. Posey receives grant/research support from Forest Pharmaceuticals and Janssen Pharmaceutica and is a consultant to Forest Pharmaceuticals.

Dr. McDougle receives grant/research support from Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., and Eli Lilly and Co., and is a consultant to or speaker for Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., Eli Lilly and Co., and Pfizer Inc.

Psychotropics^1,2 are used to manage maladaptive and interfering behaviors in 70% of patients with fragile X syndrome (FXS), the leading cause of hereditary mental retardation. Treatment tends to follow a developmental course:

• In children, stimulants and alpha-2 agonists are used for attention-deficit/hyperactivity disorder (ADHD)-like symptoms.
  
• In adolescents and adults, selective serotonin reuptake inhibitors (SSRIs) are used for anxiety/repetitive phenomena and second-generation antipsychotics (SGAs) for irritability.
  

This course—which is often effective—is based primarily on anecdotal descriptions and on rationales borrowed from studies of ADHD, obsessive-compulsive disorder (OCD), and autistic disorder/related pervasive developmental disorders (PDDs).³ Disease-modifying agents to target the underlying brain dysregulation inherent in FXS (Box)^1,4-10 are being investigated. For now, psychotropics can help you manage three common FXS symptom clusters: inattention and hyperactivity, anxiety, and aggression and self-injurious behavior (SIB).

Box

Table 1

Clinical characteristics of patients with fragile X syndrome

Physical features (seen in some males)	Long, narrow face
	High, arched palate
	Narrow inter-eye distance
	Enlarged ears
	Macro-orchidism
Behavioral symptoms	Inattention
	Hyperactivity
	Anxiety
	Repetitive behaviors
	Aggression and self-injurious behaviors (increased in adolescence and adulthood)
Comorbidities	Mental retardation (mean IQ for affected males in moderate range)
	Comorbid autism (25% of affected individuals)
	Frequent seizures (10% to 20% of affected males)
	Hypersensitivity to sensory Stimuli

Inattention and hyperactivity

Mike, age 6, has fragile X syndrome. He has been attending first grade for 4 months, and his teacher reports he does not sit still, runs throughout the classroom, and cannot focus on class work. Mike’s hyperactivity has been evident for 2 years but did not cause problems until first grade, his parents report.

Psychostimulants are the most frequently prescribed agents for inattention and hyperactivity in FXS, particularly in boys and male adolescents.¹ Among FXS patients prescribed ≥ 1 psychotropic, approximately 70% are taking a stimulant.^1,2

Efficacy. A clinical chart review found a 75% response rate in FXS children and adolescents who were given a stimulant for inattention and/or hyperactivity.¹ This is higher than the 25% to 49% stimulant response rate reported in patients with PDDs.^11,12

A 3-week, placebo-controlled, crossover trial of methylphenidate and dextroamphetamine noted a statistically significant response only to methylphenidate, with a positive response reported in 10 of 15 children (67%).¹³

Side effects. To date, limited information has described the rate of intolerable side effects associated with stimulant use in FXS,¹⁴ but in patients with PDD:

• 154 of 268 (57.5%) patient trials in a retrospective naturalistic study showed significant adverse effects with stimulant use.¹¹
  
• 13 of 72 (18%) subjects in a controlled trial discontinued methylphenidate because of adverse events (most commonly irritability).¹²
  

Based on these observations, possible side effects that deserve close monitoring include mood lability, exacerbation of anxiety, increased social withdrawal, irritability, insomnia, decreased appetite, and increased repetitive movements.

Antiadrenergics. The alpha-2 agonists clonidine and guanfacine are the second most-used class of agents for inattention and hyperactivity in FXS. As with stimulants, boys and male adolescents are most likely to receive alpha-2 agonists, with administration rates of 10% to 20%.^1,2

Efficacy. In one survey, nearly two-thirds (63%) of parents described clonidine as “very beneficial” to 35 children (mean age 6.6) with FXS.¹⁵ This is similar to a 70% response rate described for these alpha-2 agonists in a chart review.¹ These rates are much higher than the 24% response rate reported with guanfacine in a retrospective chart review of 80 children and adolescents with a PDD.¹⁶ In that review, guanfacine use was associated with reduced hyperactivity, insomnia, and tics, and increased attention.¹⁵

Side effects associated with alpha-2 agonists include lowered blood pressure and sedation.

 

L-acetylcarnitine—a carnitine derivative required for neuronal use and transport of fatty acids—is being investigated to treat hyperactivity in FXS. Hyperactive symptoms improved significantly with L-acetylcarnitine, as measured by the Conners’ Abbreviated Parent-Teacher Questionnaire, in a 1-year, placebo-controlled trial of 20 boys (mean age 9.2) with FXS.¹⁷

Discussion. Supporting evidence is limited, but clinicians are treating ADHD-like symptoms with stimulants and alpha-2 agonists in many FXS patients. Preliminary data indicate that stimulants may be more effective and better tolerated in individuals with FXS than in those with PDD.

Trying a stimulant or alpha-2 agonist for inattention or hyperactivity symptoms in a child or adolescent with FXS appears clinically appropriate, given the available evidence. Additional data based on placebo-controlled and standardized measures of treatment response are needed to help guide treatment.

We start Mike on methylphenidate, 5 mg in the morning, for inattention and hyperactivity. He tolerates this well, and after 2 weeks we increase the dosage to 5 mg bid. Several weeks into treatment, his teacher comments that he is beginning to stay in his seat and attends to some assigned tasks in the classroom.

Mike continued to tolerate methylphenidate over the next 4 years. We gradually increased the dosage as he grew and when he periodically developed breakthrough interfering symptoms in the classroom.

Anxiety symptoms

In grade school, Mike became increasingly nervous around schoolmates, teachers, and friends. His teachers commented that he repeated phrases when he appeared anxious. Other children in his special education class began to shun him; they found his perseveration odd and sometimes threatening.

Now that Mike is age 10 and in fifth grade, his parents decide that his anxiety, particularly in social settings, is interfering with his life.

Anxiety symptoms—including generalized nervousness and OCD-like obsessions and perseverations—are common psychotropic targets in FXS. Boys may be the FXS patients most often prescribed drugs for inattention and hyperactivity, but they are the least likely to receive antidepressants for anxiety symptoms.^1,2

Efficacy. More than 50% of female patients and men with FXS are prescribed SSRIs for anxiety (Table 2), and the reported response rate of 50% to 60%¹ is similar to that seen with SSRIs in autism and related disorders.¹⁸ In autism, a developmental approach is warranted, as SSRIs tend to be less effective and cause more side effects in children and adolescents than in adults.¹⁸

Adverse effects reported with SSRIs in FXS include behavioral activation, appetite changes, insomnia, and nausea.¹ In a study of fluoxetine for FXS symptoms, 10 of 35 patients (29%) had persistent side effects, most commonly weight loss and weight gain.¹⁹ One patient with pre-existing suicidal ideation worsened.

Watch for emergence or worsening of suicidal thoughts in all children and adolescents receiving antidepressants, whatever their target symptoms.

Mike is taking methylphenidate, 15 mg bid, for comorbid ADHD, and we add fluoxetine, 10 mg/d, for anxiety. This regimen is well-tolerated, so we increase fluoxetine to 20 mg/d at his 4-week follow-up appointment. After about 8 weeks, Mike’s parents report that his anxiety-associated symptoms are less severe.

Mike still appears nervous sometimes, but he uses markedly fewer perseverative phrases. This allows him to interact more meaningfully with peers and contributes to his social development.

Table 2

Target symptoms and treatment options for fragile X syndrome

Medication class	Target symptom cluster	Evidence for use of drug class in FXS
Stimulants	Inattention, hyperactivity	One placebo-controlled trial, two large clinic surveys
Alpha-2 agonists	Inattention, hyperactivity	One parent-interview report, two large clinic surveys
SSRIs	Anxiety-related symptoms	One mailed survey, two large clinic surveys
Atypical antipsychotics	Aggression, self-injury	Two large clinic surveys, several controlled trials in PDDs
FXS: fragile X syndrome
SSRIs: selective serotonin reuptake inhibitors
PDDs: pervasive developmental disorders.

Aggression and self-injury

Mike, now age 20 and participating daily in a vocational workshop, begins yelling profanities at coworkers. At his group home, he has been hitting staff at least twice a week when redirected.

He is no longer taking stimulants, having been weaned from methylphenidate several years ago, but he continues to take fluoxetine, 40 mg/d.

Fluoxetine¹⁹ and clonidine¹⁵ can decrease irritability in FXS, but atypical antipsychotics are most commonly used for aggression and SIB.^1,2 SGAs are prescribed to 10% to 20% of FXS patients who are taking medication^1,2—particularly to men—and have produced response rates of 60% to 100% when used for aggression and SIB.¹

Risperidone. No published reports have addressed using specific SGAs in FXS. In the PDD literature, most controlled data concerns risperidone.²⁰

The largest randomized, placebo-controlled trial enrolled 101 children ages 5 to 17 with autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior. Among the 49 children taking risperidone, 0.5 to 3.5 mg/d for 8 weeks, 34 (69%) were judged as treatment responders with significantly reduced irritable behavior, compared with 6 of 52 (12%) taking placebo.²¹ Risperidone therapy was associated with average weight gain of 2.7±2.9 kg, compared with 0.8±2.2 kg with placebo.

 

Besides weight gain, other significant side effects associated with risperidone include sedation and elevated serum prolactin. These effects often are more pronounced in children and adolescents than in adults with PDDs.²⁰

Other antipsychotics. Future use of SGAs in FXS will likely mirror the pattern seen in PDDs, where clinicians are moving towards weight-neutral antipsychotics such as ziprasidone and aripiprazole. In a preliminary report, aripiprazole reduced irritability in 5 youths with PDD.²² Our group is conducting a double-blind, placebo-controlled trial of aripiprazole in autism, targeting aggression, SIB, and irritability.

Discussion. SGAs are used most often in FXS to treat aggression and SIB, based on data from studies on treating similar symptoms in PDDs. Closely monitor patients for sedation, weight gain, and lipid, glucose, and prolactin elevations when using SGAs (Table 3). Be especially vigilant when children gain weight rapidly or show hyperprolactinemia signs while taking these drugs.

After being suspended from the vocational workshop, Mike is treated at a local mental health center for aggressive behaviors. He tolerates an initial dosage of aripiprazole,2.5 mg/d, which is titrated in 2.5-mg increments biweekly to 10 mg/d. At this dosage, he stops hitting staff members and his yelling of profanities is greatly reduced. Over several months, Mike returns to his vocational workshop and maintains residence at his group home.

Table 3

Medication side effects and recommended monitoring

Medication class	Side effects	Medication monitoring
Stimulants	Anorexia, insomnia, agitation, exacerbation of tics	Observe closely when starting treatment and increasing dosage
Alpha-2 agonists	Lowered blood pressure, sedation, dizziness	Observe closely when starting treatment and increasing dosage
		Check blood pressure with all dosage changes and at all clinic visits
SSRIs	Irritability, mood lability, nausea, sleep and appetite disturbances, suicidality	Observe closely when starting treatment and increasing dosage
Atypical antipsychotics	Sedation, weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, EPS, NMS, tardive dyskinesia	Obtain metabolic profile, including fasting lipids, glucose, and prolactin levels
		Monitor for weight gain and signs of EPS
EPS: extrapyramidal symptoms
NMS: neuroleptic malignant syndrome
SSRIs: selective serotonin reuptake inhibitors

Genetic-related treatments

Studies are needed to investigate the use of stimulants, SSRIs, and antipsychotics in patients with FXS unaccompanied by generalized anxiety disorder, OCD, ADHD, or PDDs. How FXS patients without those comorbidities will respond to drug treatment is unknown. Also, little also is known about possible side effects associated with combining drug treatments in individuals with FXS.

Future drug treatment in FXS will likely focus on agents that target the underlying neurochemical dysregulation associated with the FXS genotype. This approach might reduce interfering behaviors and alter the course of cognitive dysfunction—including mental retardation—associated with FXS.

Past attempts to correct FXS’ neurochemical abnormalities focused on using folic acid. The term “fragile X” describes how the X chromosome of individuals with FXS fractures in a folate-deprived medium. Many controlled trials of folic acid in FXS did not support earlier positive reports, however.⁴

Greater understanding of fragile X mental retardation protein (FMRP) function has led to the metabotropic glutamate receptor (mGluR) theory.⁷ It holds that FMRP underproduction allows exaggerated group 1 mGluR activity and leads to the FXS neurobehavioral phenotype. Researchers now are attempting to reverse the neurochemical impact of insufficient FMRP with two medication classes:

• selective group 1 mGluR receptor antagonists (mGluR5 antagonists, in particular). The mGluR5 receptor antagonist MPEP has shown the ability to rescue normal behaviors in animal models of FXS. MPEP and lithium have reversed behaviors associated with FXS and—at the microscopic level—rescued synaptic plasticity.^23,24 In the drosophila fly model of FXS, lithium reduced activity in the mGluR cascade, thus compensating for lack of FMRP.²³
  
• positive AMPA receptor modulators (ampakines) that promote activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.⁹ Excessive mGluR activity appears to impair AMPA receptors’ ability to promote cortical development, memory, and learning.⁷ Reduced AMPA receptors have been shown in the FXS mouse model,²⁵ and an ampakine is being investigated in a study of men with FXS and autism.¹
  

Related resources

• FRAXA: The Fragile X Research Foundation. Founded by parents of children with fragile X syndrome to increase funding for research toward effective treatments. www.fraxa.org.
  
• The National Fragile X Foundation. Provides educational and emotional support for fragile X families and promotes public and professional awareness. www.fragilex.org.
  
• Hagerman RJ, Hagerman PJ, eds. Fragile X syndrome: diagnosis, treatment, and research, 3rd ed. Baltimore, MD: The Johns Hopkins University Press; 2002.
  

Drug brand names

• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Guanfacine • Tenex
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Disclosures

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

Dr. Stigler receives grant/research support from Bristol-Myers Squibb Co. and Janssen Pharmaceutica.

 

Dr. Posey receives grant/research support from Forest Pharmaceuticals and Janssen Pharmaceutica and is a consultant to Forest Pharmaceuticals.

Dr. McDougle receives grant/research support from Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., and Eli Lilly and Co., and is a consultant to or speaker for Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., Eli Lilly and Co., and Pfizer Inc.

Psychotropics^1,2 are used to manage maladaptive and interfering behaviors in 70% of patients with fragile X syndrome (FXS), the leading cause of hereditary mental retardation. Treatment tends to follow a developmental course:

• In children, stimulants and alpha-2 agonists are used for attention-deficit/hyperactivity disorder (ADHD)-like symptoms.
  
• In adolescents and adults, selective serotonin reuptake inhibitors (SSRIs) are used for anxiety/repetitive phenomena and second-generation antipsychotics (SGAs) for irritability.
  

This course—which is often effective—is based primarily on anecdotal descriptions and on rationales borrowed from studies of ADHD, obsessive-compulsive disorder (OCD), and autistic disorder/related pervasive developmental disorders (PDDs).³ Disease-modifying agents to target the underlying brain dysregulation inherent in FXS (Box)^1,4-10 are being investigated. For now, psychotropics can help you manage three common FXS symptom clusters: inattention and hyperactivity, anxiety, and aggression and self-injurious behavior (SIB).

Box

Table 1

Clinical characteristics of patients with fragile X syndrome

Physical features (seen in some males)	Long, narrow face
	High, arched palate
	Narrow inter-eye distance
	Enlarged ears
	Macro-orchidism
Behavioral symptoms	Inattention
	Hyperactivity
	Anxiety
	Repetitive behaviors
	Aggression and self-injurious behaviors (increased in adolescence and adulthood)
Comorbidities	Mental retardation (mean IQ for affected males in moderate range)
	Comorbid autism (25% of affected individuals)
	Frequent seizures (10% to 20% of affected males)
	Hypersensitivity to sensory Stimuli

Inattention and hyperactivity

Mike, age 6, has fragile X syndrome. He has been attending first grade for 4 months, and his teacher reports he does not sit still, runs throughout the classroom, and cannot focus on class work. Mike’s hyperactivity has been evident for 2 years but did not cause problems until first grade, his parents report.

Psychostimulants are the most frequently prescribed agents for inattention and hyperactivity in FXS, particularly in boys and male adolescents.¹ Among FXS patients prescribed ≥ 1 psychotropic, approximately 70% are taking a stimulant.^1,2

Efficacy. A clinical chart review found a 75% response rate in FXS children and adolescents who were given a stimulant for inattention and/or hyperactivity.¹ This is higher than the 25% to 49% stimulant response rate reported in patients with PDDs.^11,12

A 3-week, placebo-controlled, crossover trial of methylphenidate and dextroamphetamine noted a statistically significant response only to methylphenidate, with a positive response reported in 10 of 15 children (67%).¹³

Side effects. To date, limited information has described the rate of intolerable side effects associated with stimulant use in FXS,¹⁴ but in patients with PDD:

• 154 of 268 (57.5%) patient trials in a retrospective naturalistic study showed significant adverse effects with stimulant use.¹¹
  
• 13 of 72 (18%) subjects in a controlled trial discontinued methylphenidate because of adverse events (most commonly irritability).¹²
  

Based on these observations, possible side effects that deserve close monitoring include mood lability, exacerbation of anxiety, increased social withdrawal, irritability, insomnia, decreased appetite, and increased repetitive movements.

Antiadrenergics. The alpha-2 agonists clonidine and guanfacine are the second most-used class of agents for inattention and hyperactivity in FXS. As with stimulants, boys and male adolescents are most likely to receive alpha-2 agonists, with administration rates of 10% to 20%.^1,2

Efficacy. In one survey, nearly two-thirds (63%) of parents described clonidine as “very beneficial” to 35 children (mean age 6.6) with FXS.¹⁵ This is similar to a 70% response rate described for these alpha-2 agonists in a chart review.¹ These rates are much higher than the 24% response rate reported with guanfacine in a retrospective chart review of 80 children and adolescents with a PDD.¹⁶ In that review, guanfacine use was associated with reduced hyperactivity, insomnia, and tics, and increased attention.¹⁵

Side effects associated with alpha-2 agonists include lowered blood pressure and sedation.

 

L-acetylcarnitine—a carnitine derivative required for neuronal use and transport of fatty acids—is being investigated to treat hyperactivity in FXS. Hyperactive symptoms improved significantly with L-acetylcarnitine, as measured by the Conners’ Abbreviated Parent-Teacher Questionnaire, in a 1-year, placebo-controlled trial of 20 boys (mean age 9.2) with FXS.¹⁷

Discussion. Supporting evidence is limited, but clinicians are treating ADHD-like symptoms with stimulants and alpha-2 agonists in many FXS patients. Preliminary data indicate that stimulants may be more effective and better tolerated in individuals with FXS than in those with PDD.

Trying a stimulant or alpha-2 agonist for inattention or hyperactivity symptoms in a child or adolescent with FXS appears clinically appropriate, given the available evidence. Additional data based on placebo-controlled and standardized measures of treatment response are needed to help guide treatment.

We start Mike on methylphenidate, 5 mg in the morning, for inattention and hyperactivity. He tolerates this well, and after 2 weeks we increase the dosage to 5 mg bid. Several weeks into treatment, his teacher comments that he is beginning to stay in his seat and attends to some assigned tasks in the classroom.

Mike continued to tolerate methylphenidate over the next 4 years. We gradually increased the dosage as he grew and when he periodically developed breakthrough interfering symptoms in the classroom.

Anxiety symptoms

In grade school, Mike became increasingly nervous around schoolmates, teachers, and friends. His teachers commented that he repeated phrases when he appeared anxious. Other children in his special education class began to shun him; they found his perseveration odd and sometimes threatening.

Now that Mike is age 10 and in fifth grade, his parents decide that his anxiety, particularly in social settings, is interfering with his life.

Anxiety symptoms—including generalized nervousness and OCD-like obsessions and perseverations—are common psychotropic targets in FXS. Boys may be the FXS patients most often prescribed drugs for inattention and hyperactivity, but they are the least likely to receive antidepressants for anxiety symptoms.^1,2

Efficacy. More than 50% of female patients and men with FXS are prescribed SSRIs for anxiety (Table 2), and the reported response rate of 50% to 60%¹ is similar to that seen with SSRIs in autism and related disorders.¹⁸ In autism, a developmental approach is warranted, as SSRIs tend to be less effective and cause more side effects in children and adolescents than in adults.¹⁸

Adverse effects reported with SSRIs in FXS include behavioral activation, appetite changes, insomnia, and nausea.¹ In a study of fluoxetine for FXS symptoms, 10 of 35 patients (29%) had persistent side effects, most commonly weight loss and weight gain.¹⁹ One patient with pre-existing suicidal ideation worsened.

Watch for emergence or worsening of suicidal thoughts in all children and adolescents receiving antidepressants, whatever their target symptoms.

Mike is taking methylphenidate, 15 mg bid, for comorbid ADHD, and we add fluoxetine, 10 mg/d, for anxiety. This regimen is well-tolerated, so we increase fluoxetine to 20 mg/d at his 4-week follow-up appointment. After about 8 weeks, Mike’s parents report that his anxiety-associated symptoms are less severe.

Mike still appears nervous sometimes, but he uses markedly fewer perseverative phrases. This allows him to interact more meaningfully with peers and contributes to his social development.

Table 2

Target symptoms and treatment options for fragile X syndrome

Medication class	Target symptom cluster	Evidence for use of drug class in FXS
Stimulants	Inattention, hyperactivity	One placebo-controlled trial, two large clinic surveys
Alpha-2 agonists	Inattention, hyperactivity	One parent-interview report, two large clinic surveys
SSRIs	Anxiety-related symptoms	One mailed survey, two large clinic surveys
Atypical antipsychotics	Aggression, self-injury	Two large clinic surveys, several controlled trials in PDDs
FXS: fragile X syndrome
SSRIs: selective serotonin reuptake inhibitors
PDDs: pervasive developmental disorders.

Aggression and self-injury

Mike, now age 20 and participating daily in a vocational workshop, begins yelling profanities at coworkers. At his group home, he has been hitting staff at least twice a week when redirected.

He is no longer taking stimulants, having been weaned from methylphenidate several years ago, but he continues to take fluoxetine, 40 mg/d.

Fluoxetine¹⁹ and clonidine¹⁵ can decrease irritability in FXS, but atypical antipsychotics are most commonly used for aggression and SIB.^1,2 SGAs are prescribed to 10% to 20% of FXS patients who are taking medication^1,2—particularly to men—and have produced response rates of 60% to 100% when used for aggression and SIB.¹

Risperidone. No published reports have addressed using specific SGAs in FXS. In the PDD literature, most controlled data concerns risperidone.²⁰

The largest randomized, placebo-controlled trial enrolled 101 children ages 5 to 17 with autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior. Among the 49 children taking risperidone, 0.5 to 3.5 mg/d for 8 weeks, 34 (69%) were judged as treatment responders with significantly reduced irritable behavior, compared with 6 of 52 (12%) taking placebo.²¹ Risperidone therapy was associated with average weight gain of 2.7±2.9 kg, compared with 0.8±2.2 kg with placebo.

 

Besides weight gain, other significant side effects associated with risperidone include sedation and elevated serum prolactin. These effects often are more pronounced in children and adolescents than in adults with PDDs.²⁰

Other antipsychotics. Future use of SGAs in FXS will likely mirror the pattern seen in PDDs, where clinicians are moving towards weight-neutral antipsychotics such as ziprasidone and aripiprazole. In a preliminary report, aripiprazole reduced irritability in 5 youths with PDD.²² Our group is conducting a double-blind, placebo-controlled trial of aripiprazole in autism, targeting aggression, SIB, and irritability.

Discussion. SGAs are used most often in FXS to treat aggression and SIB, based on data from studies on treating similar symptoms in PDDs. Closely monitor patients for sedation, weight gain, and lipid, glucose, and prolactin elevations when using SGAs (Table 3). Be especially vigilant when children gain weight rapidly or show hyperprolactinemia signs while taking these drugs.

After being suspended from the vocational workshop, Mike is treated at a local mental health center for aggressive behaviors. He tolerates an initial dosage of aripiprazole,2.5 mg/d, which is titrated in 2.5-mg increments biweekly to 10 mg/d. At this dosage, he stops hitting staff members and his yelling of profanities is greatly reduced. Over several months, Mike returns to his vocational workshop and maintains residence at his group home.

Table 3

Medication side effects and recommended monitoring

Medication class	Side effects	Medication monitoring
Stimulants	Anorexia, insomnia, agitation, exacerbation of tics	Observe closely when starting treatment and increasing dosage
Alpha-2 agonists	Lowered blood pressure, sedation, dizziness	Observe closely when starting treatment and increasing dosage
		Check blood pressure with all dosage changes and at all clinic visits
SSRIs	Irritability, mood lability, nausea, sleep and appetite disturbances, suicidality	Observe closely when starting treatment and increasing dosage
Atypical antipsychotics	Sedation, weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, EPS, NMS, tardive dyskinesia	Obtain metabolic profile, including fasting lipids, glucose, and prolactin levels
		Monitor for weight gain and signs of EPS
EPS: extrapyramidal symptoms
NMS: neuroleptic malignant syndrome
SSRIs: selective serotonin reuptake inhibitors

Genetic-related treatments

Studies are needed to investigate the use of stimulants, SSRIs, and antipsychotics in patients with FXS unaccompanied by generalized anxiety disorder, OCD, ADHD, or PDDs. How FXS patients without those comorbidities will respond to drug treatment is unknown. Also, little also is known about possible side effects associated with combining drug treatments in individuals with FXS.

Future drug treatment in FXS will likely focus on agents that target the underlying neurochemical dysregulation associated with the FXS genotype. This approach might reduce interfering behaviors and alter the course of cognitive dysfunction—including mental retardation—associated with FXS.

Past attempts to correct FXS’ neurochemical abnormalities focused on using folic acid. The term “fragile X” describes how the X chromosome of individuals with FXS fractures in a folate-deprived medium. Many controlled trials of folic acid in FXS did not support earlier positive reports, however.⁴

Greater understanding of fragile X mental retardation protein (FMRP) function has led to the metabotropic glutamate receptor (mGluR) theory.⁷ It holds that FMRP underproduction allows exaggerated group 1 mGluR activity and leads to the FXS neurobehavioral phenotype. Researchers now are attempting to reverse the neurochemical impact of insufficient FMRP with two medication classes:

• selective group 1 mGluR receptor antagonists (mGluR5 antagonists, in particular). The mGluR5 receptor antagonist MPEP has shown the ability to rescue normal behaviors in animal models of FXS. MPEP and lithium have reversed behaviors associated with FXS and—at the microscopic level—rescued synaptic plasticity.^23,24 In the drosophila fly model of FXS, lithium reduced activity in the mGluR cascade, thus compensating for lack of FMRP.²³
  
• positive AMPA receptor modulators (ampakines) that promote activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.⁹ Excessive mGluR activity appears to impair AMPA receptors’ ability to promote cortical development, memory, and learning.⁷ Reduced AMPA receptors have been shown in the FXS mouse model,²⁵ and an ampakine is being investigated in a study of men with FXS and autism.¹
  

Related resources

• FRAXA: The Fragile X Research Foundation. Founded by parents of children with fragile X syndrome to increase funding for research toward effective treatments. www.fraxa.org.
  
• The National Fragile X Foundation. Provides educational and emotional support for fragile X families and promotes public and professional awareness. www.fragilex.org.
  
• Hagerman RJ, Hagerman PJ, eds. Fragile X syndrome: diagnosis, treatment, and research, 3rd ed. Baltimore, MD: The Johns Hopkins University Press; 2002.
  

Drug brand names

• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Guanfacine • Tenex
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Disclosures

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

Dr. Stigler receives grant/research support from Bristol-Myers Squibb Co. and Janssen Pharmaceutica.

 

Dr. Posey receives grant/research support from Forest Pharmaceuticals and Janssen Pharmaceutica and is a consultant to Forest Pharmaceuticals.

Dr. McDougle receives grant/research support from Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., and Eli Lilly and Co., and is a consultant to or speaker for Forest Pharmaceuticals, Janssen Pharmaceutica, Bristol-Myers Squibb Co., Eli Lilly and Co., and Pfizer Inc.

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• 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.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

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 grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

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 Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• 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.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

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 grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

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 Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• 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.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

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 grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

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 Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).