Lisa Wiggins, MS

Antipsychotics—particularly the atypicals—have therapeutic properties that make them potential candidates for treating a variety of disorders in children and adolescents. As has occurred in adults, the use of atypical antipsychotics is expanding beyond schizophrenia to pediatric affective and nonpsychotic conditions.

In part 1 of this article, we examined the evidence for using atypical antipsychotics in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. Our search of the literature suggested two concerns to keep in mind when prescribing antipsychotics to children and adolescents:

• Side effects—weight gain, metabolic disturbances, hyperprolactinemia, and cardiac conduction abnormalities—are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to atypical antipsychotics.
• Administering medications to children and adolescents requires special precautions because younger patients respond differently than do adults to psychotropic medications.

In part 2, we look at more limited evidence for using atypicals in children with anxiety disorders, autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa (Box 1)^1-3, and stuttering (Box 2)⁴.

Box 1

Anxiety disorders: Limited use for antipsychotics

Anxiety disorders are among the most prevalent psychopathologies in the pediatric population, and current treatment recommendations strongly focus on psychotherapeutic interventions. Pharmacologic interventions, however—including imipramine, selective serotonin reuptake inhibitors, and even benzodiazepines—can offer an important adjunct to behavioral and other nonpharmacologic therapies, particularly at the onset of illness and before behavioral techniques are learned.

The American Academy of Child and Adolescent Psychiatry’s 1997 practice parameters for anxiety disorders do not recommend using neuroleptics in the absence of comorbidity—such as Tourette’s syndrome or psychosis—because of concerns about impaired cognition and tardive dyskinesia.⁵ The clinician should also be aware that “neuroleptic separation anxiety syndrome” has been described in children who developed school phobia in response to haloperidol or pimozide while being treated for Tourette’s disorder.

Similar reports describe separation anxiety in two adolescent boys and one prepubertal boy treated with adjunctive low-dose risperidone for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and behavioral disruption. Two of the boys were subsequently treated with olanzapine without a recurrence of anxiety.

It seems unlikely that atypical antipsychotics will play a significant role in managing pediatric anxiety. Controlled studies for this indication are limited. Alternate pharmacologic options are considered safer and are themselves recommended only as adjuncts to other interventions.

Clinicians will no doubt be tempted to try atypicals in lieu of benzodiazepines for severe OCD (and perhaps even for severe anxiety) in this young population. If an antipsychotic trial is initiated, we recommend clear documentation of poor response to other interventions, notations of comorbidity, judicious dosing, and close monitoring. Psychotic symptoms associated with posttraumatic stress disorder may be a reasonable indication for antipsychotic use, but more research is needed.

Autism: Improving behavioral symptoms

Pharmacotherapy for children with autism and pervasive developmental disorders (PDD) generally targets aggression, irritability, stereotypic behavior, hyperactivity, self-abusive behavior, and self-stimulatory behavior. Almost all classes of psychotropics—including antipsychotics, selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, mood stabilizers, and anxiolytics—have been tested in clinical trials, with varying degrees of success.

Haloperidol has been shown to improve behavioral symptoms, including educational learning.⁶ Dyskinesias—including tardive dyskinesia—remain a concern, however, with long-term use of haloperidol in children.

Recently, attention has turned to atypical antipsychotics, with their lower risk of extrapyramidal symptoms (EPS). Double-blind, placebo-controlled studies have demonstrated the efficacy of these agents in treating autistic and developmental disorders; risperidone and olanzapine have been studied most extensively.

Risperidone. A 16-week open-label trial of 24 children ages 3 to 6 with autistic disorders demonstrated modest improvement with risperidone, 0.5 mg/d. At least 25% improvement was seen in:

 

• the Children’s Psychiatric Rating Scale (CPRS)
• hyperactivity, fidgetiness, rhythmic motions, mood lability, and angry affect, as measured by the Childhood Autism Rating Scale (CARS)
• functional impairment, as determined by the Children’s Global Assessment Scale (C-GAS).

Overall, risperidone was well-tolerated at this low dosage, although two children did not complete the study because of side effects. Three children gained more than 10% of their body weight.⁷

In a 12-month semi-naturalistic prospective study, 11 children and adolescents ages 7 to 17 (mean age 12.3) with autism (n=9) or PDD (n=2) were treated with risperidone. Starting dosage was 0.5 mg/d, mean dosage was 2.7 mg/d, and maximum dosage was 6 mg/d (0.1/mg/kg/d). Behavioral symptoms improved significantly with risperidone in 10 of the 11 subjects during the first 6 months of treatment. Autism’s core symptoms were also mildly improved, although more slowly and later in treatment. Risperidone continued to work in patients treated for 12 months, whereas behavioral symptoms reemerged in those who discontinued drug therapy after 6 months. Weight gain was the most common side effect.

After 6 months of therapy two patients developed facial dystonia, which resolved after the risperidone dosage was reduced or discontinued. Amenorrhea was observed in one patient, but no changes were reported in liver function, blood tests, or electrocardiogram (ECG) readings.⁸

Box 2

Others have contributed greatly to our understanding of using atypicals in treating autism and PDD.^9,10 Posey et al reported using risperidone to treat two boys, ages 23 months and 29 months. In both cases, aggression was reduced and social relatedness improved significantly. One patient’s treatment was complicated by dose-related presistent tachycardia and QTc prolongation.⁹

McDougle conducted an initial prospective, 12-week, open-label study examining risperidone treatment in 18 children and adolescents (15 boys and 3 girls, mean age 10) with PDD,¹⁰ followed by an 8-week, double-blind, placebo-controlled study of risperidone in 100 children with autistic disorders (excluding Asperger’s disorder).¹¹ Mean dosage was 2.1 mg/d (0.75 mg to 3.5 mg/d) divided into two doses. The study examined the benefit in a relatively young cohort (Tanner stages I and II—children who have yet to complete sexual development).

After 2 to 4 weeks of treatment, irritability improved most significantly (>25% improvement on the Aberrant Behavior Checklist), and stereotypic behavior also improved. Inappropriate speech patterns did not change. Anecdotal reports suggested that social relatedness improved, although quantitative evaluation was inconclusive. EPS, as measured by the Simpson Angus EPS score, were mild and generally seen in early treatment. Side effects included increased appetite, weight gain, decreased energy, and sedation.¹¹

Olanzapine. Most studies of olanzapine in children and adolescents with autistic disorders have been open-label:

Eight patients (four adults, ages 18 to 42, and four children, ages 5 to 17) were treated with olanzapine, mean dosage 7.8 mg/d for 12 weeks. Seven completed the study, and six were rated “much improved” or “very much improved” on the global improvement item of the Clinical Global Impression (CGI) scale. Hyperactivity, aggression, anger, and self-injurious behavior improved significantly, as did social relatedness, affectual reactions, sensory responses, and language use. The drug was well tolerated, with the most significant side effect being increased appetite and weight gain (mean increase 8.3 kg).¹²

In an open-label pilot study, 12 children with autism (mean age 8) were randomly assigned to 6 weeks of treatment with olanzapine (mean final dosage 7.9 mg/d) or haloperidol (mean final dosage 1.4 mg/d). Symptoms were reduced in both groups. Five of six children in the olanzapine group and three of six children in the haloperidol group were noted as responders, according to the CGI improvement item and the Children’s Psychiatric Rating Scale (CPRS) Autism Factor. Drowsiness and weight gain were seen with olanzapine.¹³

Similar results were obtained in another study, with significant improvements in irritability, hyperactivity, and excessive speech, as evaluated by the Aberrant Behavior Checklist.^14,15

Summary. Atypical antipsychotics appear to be effective and well tolerated in children and adolescents with autistic and developmental disorders. Double-blind, placebo-controlled studies confirm the benefit of risperidone; open-label trials likewise suggest the benefit of olanzapine. Research is limited on quetiapine and ziprasidone in this population.

Weight gain appears to be the most problematic side effect and should be monitored. Early dietary education and discussion with the patient, parents, and family can help keep weight gain to a minimum.

 

Tourette’s disorder: Modest benefit

Tourette’s disorder and simple motor or vocal tics have traditionally been treated with the older neuroleptics, particularly haloperidol and pimozide. These agents have fallen out of favor in younger patients, however, because of the risk of short- and long-term side effects, including EPS, tardive dyskinesia, cognitive blunting, and school phobia.

Clinicians have turned to alternate agents, such as clonidine and guanfacine (alpha-2 agonists) to treat tic disorders, and now are trying atypical antipsychotics. In open and controlled studies, the atypicals have demonstrated moderate improvement in Tourette’s disorder. Even so, none of the newer agents has shown benefits comparable to haloperidol, which recently demonstrated 66% improvement in tic symptoms when compared with a placebo.¹⁶ For example:

• ziprasidone—35% improvement in tic symptoms when compared with a placebo¹⁷
• risperidone—44% improvement when compared with a placebo in 17 pediatric patients¹⁸
• clozapine—no effect on tic symptoms¹⁶ (clozapine causes little or no dopamine [D2] blockade, which most likely explains this result)
• olanzapine—modest to moderate benefit, but somewhat less effective than risperidone or ziprasidone (small sample size and inclusion of adult patients have confounded interpretation in the studies examining response to risperidone and olanzapine).^16,17

Sedation was the most common side effect seen with use of risperidone, ziprasidone, or olanzapine, and weight gain was particularly problematic with olanzapine.¹⁶ No ECG abnormalities were noted in the 28 children treated with ziprasidone.¹⁷

Disruptive behavior: Improved conduct

The disruptive behavior disorders of childhood and adolescence include conduct disorder and oppositional defiant disorder. The only two antipsychotic medications approved to treat behavioral symptoms are chlorpromazine and thioridazine. These indications were approved in the 1980s, based on limited trials with poor statistical comparison and controlled study groups. Moreover, thioridazine has since been issued a black-box warning because of concerns about cardiac complications from QTc prolongation.

Among the typical antipsychotics, haloperidol has been studied the most extensively in disruptive behavior disorders, although it is not FDA-approved for this indication. Haloperidol has decreased destructive and aggressive behavior, oppositionality, and hostility, and has improved scores on children’s psychiatric and CGI scales.¹⁹

More recent studies have examined the role of atypical antipsychotics in disruptive behavior disorders, primarily risperidone.

Risperidone. In a double-blind, placebo-controlled study, use of risperidone (average dosage 0.75 to 1.50 mg/d) improved aggression and delinquent behavior in 20 children, ages 5 to 15, diagnosed with conduct disorder.²⁰ In a larger 6-week, multisite, double-blind, placebo-controlled study, researchers examined the use of risperidone (mean dosage 1.11 mg/kg/d) in 118 children with conduct problems and borderline intellectual functioning (60% had oppositional defiant disorder, 40% had conduct disorder, and 60% had ADHD). Behaviors—anxious, hyperactive, self-injurious, isolative, and stereotypic—improved, as did adaptive skills. The most common side effects were sedation, GI distress, weight gain, hyperprolactinemia, rhinitis, and headaches.²¹ Replication of this study produced similar findings.²²

In an extension study of conduct disorder, 34 children ages 5 to 14 with comorbid borderline intellectual functioning were treated for approximately 1 year with risperidone (mean dosage 1.48 mg/d). Clinical benefit, defined by statistically significant improvement in the conduct problem subscale of the Nisonger Child Behavior Rating Form, was noted throughout the study. Prolactin levels were elevated after 3 months of treatment but declined thereafter.²³

No controlled studies have been published using olanzapine in children and adolescents with disruptive behavior disorders. As other medications—lithium, anticonvulsants, and psychostimulants—are available for symptomatic treatment of this population, questions remain. Are antipsychotics the best class of medication for this purpose, and should they be tried as first-line therapy? Few studies have compared the efficacy of antipsychotics and other pharmacologic options.

Summary

Pharmacotherapy of childhood psychiatric conditions is complex and an extremely underdeveloped area of research. Even so, clinicians are experimenting with the use of atypical antipsychotics on a trial-and-error basis or as adjuncts to other medications for childhood conditions beyond schizophrenia.²⁴

Even more than in adult populations, judicious use of atypical antipsychotics is warranted in children and adolescents because of potential long-term consequences. The risk of interfering with normal development and the unique pharmacokinetics of childhood are important considerations. At the same time, atypical antipsychotics may offer the potential to improve behavior and function in children with intractable psychiatric conditions.

Related resources

• Pappadopulas E, Jensen PS, Schur SB, et al. Real world atypical antipsychotic prescribing practices in public child and adolescent inpatient settings. Schizophr Bull 2002;28(1):111-121.
• Malone RP, Sheikh R, Zito JM. Novel antipsychotic medications is the treatment of children and adolescents. Psychiatr Serv 1999; 50(2):171-174.

Drug brand names

• Chlorpromazine • Thorazine
• Clonidine • Catapres
• Clozapine • Clozaril
• Guanfacine • Tenex
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

 

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Antipsychotics—particularly the atypicals—have therapeutic properties that make them potential candidates for treating a variety of disorders in children and adolescents. As has occurred in adults, the use of atypical antipsychotics is expanding beyond schizophrenia to pediatric affective and nonpsychotic conditions.

In part 1 of this article, we examined the evidence for using atypical antipsychotics in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. Our search of the literature suggested two concerns to keep in mind when prescribing antipsychotics to children and adolescents:

• Side effects—weight gain, metabolic disturbances, hyperprolactinemia, and cardiac conduction abnormalities—are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to atypical antipsychotics.
• Administering medications to children and adolescents requires special precautions because younger patients respond differently than do adults to psychotropic medications.

In part 2, we look at more limited evidence for using atypicals in children with anxiety disorders, autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa (Box 1)^1-3, and stuttering (Box 2)⁴.

Box 1

Anxiety disorders: Limited use for antipsychotics

Anxiety disorders are among the most prevalent psychopathologies in the pediatric population, and current treatment recommendations strongly focus on psychotherapeutic interventions. Pharmacologic interventions, however—including imipramine, selective serotonin reuptake inhibitors, and even benzodiazepines—can offer an important adjunct to behavioral and other nonpharmacologic therapies, particularly at the onset of illness and before behavioral techniques are learned.

The American Academy of Child and Adolescent Psychiatry’s 1997 practice parameters for anxiety disorders do not recommend using neuroleptics in the absence of comorbidity—such as Tourette’s syndrome or psychosis—because of concerns about impaired cognition and tardive dyskinesia.⁵ The clinician should also be aware that “neuroleptic separation anxiety syndrome” has been described in children who developed school phobia in response to haloperidol or pimozide while being treated for Tourette’s disorder.

Similar reports describe separation anxiety in two adolescent boys and one prepubertal boy treated with adjunctive low-dose risperidone for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and behavioral disruption. Two of the boys were subsequently treated with olanzapine without a recurrence of anxiety.

It seems unlikely that atypical antipsychotics will play a significant role in managing pediatric anxiety. Controlled studies for this indication are limited. Alternate pharmacologic options are considered safer and are themselves recommended only as adjuncts to other interventions.

Clinicians will no doubt be tempted to try atypicals in lieu of benzodiazepines for severe OCD (and perhaps even for severe anxiety) in this young population. If an antipsychotic trial is initiated, we recommend clear documentation of poor response to other interventions, notations of comorbidity, judicious dosing, and close monitoring. Psychotic symptoms associated with posttraumatic stress disorder may be a reasonable indication for antipsychotic use, but more research is needed.

Autism: Improving behavioral symptoms

Pharmacotherapy for children with autism and pervasive developmental disorders (PDD) generally targets aggression, irritability, stereotypic behavior, hyperactivity, self-abusive behavior, and self-stimulatory behavior. Almost all classes of psychotropics—including antipsychotics, selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, mood stabilizers, and anxiolytics—have been tested in clinical trials, with varying degrees of success.

Haloperidol has been shown to improve behavioral symptoms, including educational learning.⁶ Dyskinesias—including tardive dyskinesia—remain a concern, however, with long-term use of haloperidol in children.

Recently, attention has turned to atypical antipsychotics, with their lower risk of extrapyramidal symptoms (EPS). Double-blind, placebo-controlled studies have demonstrated the efficacy of these agents in treating autistic and developmental disorders; risperidone and olanzapine have been studied most extensively.

Risperidone. A 16-week open-label trial of 24 children ages 3 to 6 with autistic disorders demonstrated modest improvement with risperidone, 0.5 mg/d. At least 25% improvement was seen in:

 

• the Children’s Psychiatric Rating Scale (CPRS)
• hyperactivity, fidgetiness, rhythmic motions, mood lability, and angry affect, as measured by the Childhood Autism Rating Scale (CARS)
• functional impairment, as determined by the Children’s Global Assessment Scale (C-GAS).

Overall, risperidone was well-tolerated at this low dosage, although two children did not complete the study because of side effects. Three children gained more than 10% of their body weight.⁷

In a 12-month semi-naturalistic prospective study, 11 children and adolescents ages 7 to 17 (mean age 12.3) with autism (n=9) or PDD (n=2) were treated with risperidone. Starting dosage was 0.5 mg/d, mean dosage was 2.7 mg/d, and maximum dosage was 6 mg/d (0.1/mg/kg/d). Behavioral symptoms improved significantly with risperidone in 10 of the 11 subjects during the first 6 months of treatment. Autism’s core symptoms were also mildly improved, although more slowly and later in treatment. Risperidone continued to work in patients treated for 12 months, whereas behavioral symptoms reemerged in those who discontinued drug therapy after 6 months. Weight gain was the most common side effect.

After 6 months of therapy two patients developed facial dystonia, which resolved after the risperidone dosage was reduced or discontinued. Amenorrhea was observed in one patient, but no changes were reported in liver function, blood tests, or electrocardiogram (ECG) readings.⁸

Box 2

Others have contributed greatly to our understanding of using atypicals in treating autism and PDD.^9,10 Posey et al reported using risperidone to treat two boys, ages 23 months and 29 months. In both cases, aggression was reduced and social relatedness improved significantly. One patient’s treatment was complicated by dose-related presistent tachycardia and QTc prolongation.⁹

McDougle conducted an initial prospective, 12-week, open-label study examining risperidone treatment in 18 children and adolescents (15 boys and 3 girls, mean age 10) with PDD,¹⁰ followed by an 8-week, double-blind, placebo-controlled study of risperidone in 100 children with autistic disorders (excluding Asperger’s disorder).¹¹ Mean dosage was 2.1 mg/d (0.75 mg to 3.5 mg/d) divided into two doses. The study examined the benefit in a relatively young cohort (Tanner stages I and II—children who have yet to complete sexual development).

After 2 to 4 weeks of treatment, irritability improved most significantly (>25% improvement on the Aberrant Behavior Checklist), and stereotypic behavior also improved. Inappropriate speech patterns did not change. Anecdotal reports suggested that social relatedness improved, although quantitative evaluation was inconclusive. EPS, as measured by the Simpson Angus EPS score, were mild and generally seen in early treatment. Side effects included increased appetite, weight gain, decreased energy, and sedation.¹¹

Olanzapine. Most studies of olanzapine in children and adolescents with autistic disorders have been open-label:

Eight patients (four adults, ages 18 to 42, and four children, ages 5 to 17) were treated with olanzapine, mean dosage 7.8 mg/d for 12 weeks. Seven completed the study, and six were rated “much improved” or “very much improved” on the global improvement item of the Clinical Global Impression (CGI) scale. Hyperactivity, aggression, anger, and self-injurious behavior improved significantly, as did social relatedness, affectual reactions, sensory responses, and language use. The drug was well tolerated, with the most significant side effect being increased appetite and weight gain (mean increase 8.3 kg).¹²

In an open-label pilot study, 12 children with autism (mean age 8) were randomly assigned to 6 weeks of treatment with olanzapine (mean final dosage 7.9 mg/d) or haloperidol (mean final dosage 1.4 mg/d). Symptoms were reduced in both groups. Five of six children in the olanzapine group and three of six children in the haloperidol group were noted as responders, according to the CGI improvement item and the Children’s Psychiatric Rating Scale (CPRS) Autism Factor. Drowsiness and weight gain were seen with olanzapine.¹³

Similar results were obtained in another study, with significant improvements in irritability, hyperactivity, and excessive speech, as evaluated by the Aberrant Behavior Checklist.^14,15

Summary. Atypical antipsychotics appear to be effective and well tolerated in children and adolescents with autistic and developmental disorders. Double-blind, placebo-controlled studies confirm the benefit of risperidone; open-label trials likewise suggest the benefit of olanzapine. Research is limited on quetiapine and ziprasidone in this population.

Weight gain appears to be the most problematic side effect and should be monitored. Early dietary education and discussion with the patient, parents, and family can help keep weight gain to a minimum.

 

Tourette’s disorder: Modest benefit

Tourette’s disorder and simple motor or vocal tics have traditionally been treated with the older neuroleptics, particularly haloperidol and pimozide. These agents have fallen out of favor in younger patients, however, because of the risk of short- and long-term side effects, including EPS, tardive dyskinesia, cognitive blunting, and school phobia.

Clinicians have turned to alternate agents, such as clonidine and guanfacine (alpha-2 agonists) to treat tic disorders, and now are trying atypical antipsychotics. In open and controlled studies, the atypicals have demonstrated moderate improvement in Tourette’s disorder. Even so, none of the newer agents has shown benefits comparable to haloperidol, which recently demonstrated 66% improvement in tic symptoms when compared with a placebo.¹⁶ For example:

• ziprasidone—35% improvement in tic symptoms when compared with a placebo¹⁷
• risperidone—44% improvement when compared with a placebo in 17 pediatric patients¹⁸
• clozapine—no effect on tic symptoms¹⁶ (clozapine causes little or no dopamine [D2] blockade, which most likely explains this result)
• olanzapine—modest to moderate benefit, but somewhat less effective than risperidone or ziprasidone (small sample size and inclusion of adult patients have confounded interpretation in the studies examining response to risperidone and olanzapine).^16,17

Sedation was the most common side effect seen with use of risperidone, ziprasidone, or olanzapine, and weight gain was particularly problematic with olanzapine.¹⁶ No ECG abnormalities were noted in the 28 children treated with ziprasidone.¹⁷

Disruptive behavior: Improved conduct

The disruptive behavior disorders of childhood and adolescence include conduct disorder and oppositional defiant disorder. The only two antipsychotic medications approved to treat behavioral symptoms are chlorpromazine and thioridazine. These indications were approved in the 1980s, based on limited trials with poor statistical comparison and controlled study groups. Moreover, thioridazine has since been issued a black-box warning because of concerns about cardiac complications from QTc prolongation.

Among the typical antipsychotics, haloperidol has been studied the most extensively in disruptive behavior disorders, although it is not FDA-approved for this indication. Haloperidol has decreased destructive and aggressive behavior, oppositionality, and hostility, and has improved scores on children’s psychiatric and CGI scales.¹⁹

More recent studies have examined the role of atypical antipsychotics in disruptive behavior disorders, primarily risperidone.

Risperidone. In a double-blind, placebo-controlled study, use of risperidone (average dosage 0.75 to 1.50 mg/d) improved aggression and delinquent behavior in 20 children, ages 5 to 15, diagnosed with conduct disorder.²⁰ In a larger 6-week, multisite, double-blind, placebo-controlled study, researchers examined the use of risperidone (mean dosage 1.11 mg/kg/d) in 118 children with conduct problems and borderline intellectual functioning (60% had oppositional defiant disorder, 40% had conduct disorder, and 60% had ADHD). Behaviors—anxious, hyperactive, self-injurious, isolative, and stereotypic—improved, as did adaptive skills. The most common side effects were sedation, GI distress, weight gain, hyperprolactinemia, rhinitis, and headaches.²¹ Replication of this study produced similar findings.²²

In an extension study of conduct disorder, 34 children ages 5 to 14 with comorbid borderline intellectual functioning were treated for approximately 1 year with risperidone (mean dosage 1.48 mg/d). Clinical benefit, defined by statistically significant improvement in the conduct problem subscale of the Nisonger Child Behavior Rating Form, was noted throughout the study. Prolactin levels were elevated after 3 months of treatment but declined thereafter.²³

No controlled studies have been published using olanzapine in children and adolescents with disruptive behavior disorders. As other medications—lithium, anticonvulsants, and psychostimulants—are available for symptomatic treatment of this population, questions remain. Are antipsychotics the best class of medication for this purpose, and should they be tried as first-line therapy? Few studies have compared the efficacy of antipsychotics and other pharmacologic options.

Summary

Pharmacotherapy of childhood psychiatric conditions is complex and an extremely underdeveloped area of research. Even so, clinicians are experimenting with the use of atypical antipsychotics on a trial-and-error basis or as adjuncts to other medications for childhood conditions beyond schizophrenia.²⁴

Even more than in adult populations, judicious use of atypical antipsychotics is warranted in children and adolescents because of potential long-term consequences. The risk of interfering with normal development and the unique pharmacokinetics of childhood are important considerations. At the same time, atypical antipsychotics may offer the potential to improve behavior and function in children with intractable psychiatric conditions.

Related resources

• Pappadopulas E, Jensen PS, Schur SB, et al. Real world atypical antipsychotic prescribing practices in public child and adolescent inpatient settings. Schizophr Bull 2002;28(1):111-121.
• Malone RP, Sheikh R, Zito JM. Novel antipsychotic medications is the treatment of children and adolescents. Psychiatr Serv 1999; 50(2):171-174.

Drug brand names

• Chlorpromazine • Thorazine
• Clonidine • Catapres
• Clozapine • Clozaril
• Guanfacine • Tenex
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

 

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Antipsychotics—particularly the atypicals—have therapeutic properties that make them potential candidates for treating a variety of disorders in children and adolescents. As has occurred in adults, the use of atypical antipsychotics is expanding beyond schizophrenia to pediatric affective and nonpsychotic conditions.

In part 1 of this article, we examined the evidence for using atypical antipsychotics in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. Our search of the literature suggested two concerns to keep in mind when prescribing antipsychotics to children and adolescents:

• Side effects—weight gain, metabolic disturbances, hyperprolactinemia, and cardiac conduction abnormalities—are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to atypical antipsychotics.
• Administering medications to children and adolescents requires special precautions because younger patients respond differently than do adults to psychotropic medications.

In part 2, we look at more limited evidence for using atypicals in children with anxiety disorders, autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa (Box 1)^1-3, and stuttering (Box 2)⁴.

Box 1

Anxiety disorders: Limited use for antipsychotics

Anxiety disorders are among the most prevalent psychopathologies in the pediatric population, and current treatment recommendations strongly focus on psychotherapeutic interventions. Pharmacologic interventions, however—including imipramine, selective serotonin reuptake inhibitors, and even benzodiazepines—can offer an important adjunct to behavioral and other nonpharmacologic therapies, particularly at the onset of illness and before behavioral techniques are learned.

The American Academy of Child and Adolescent Psychiatry’s 1997 practice parameters for anxiety disorders do not recommend using neuroleptics in the absence of comorbidity—such as Tourette’s syndrome or psychosis—because of concerns about impaired cognition and tardive dyskinesia.⁵ The clinician should also be aware that “neuroleptic separation anxiety syndrome” has been described in children who developed school phobia in response to haloperidol or pimozide while being treated for Tourette’s disorder.

Similar reports describe separation anxiety in two adolescent boys and one prepubertal boy treated with adjunctive low-dose risperidone for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and behavioral disruption. Two of the boys were subsequently treated with olanzapine without a recurrence of anxiety.

It seems unlikely that atypical antipsychotics will play a significant role in managing pediatric anxiety. Controlled studies for this indication are limited. Alternate pharmacologic options are considered safer and are themselves recommended only as adjuncts to other interventions.

Clinicians will no doubt be tempted to try atypicals in lieu of benzodiazepines for severe OCD (and perhaps even for severe anxiety) in this young population. If an antipsychotic trial is initiated, we recommend clear documentation of poor response to other interventions, notations of comorbidity, judicious dosing, and close monitoring. Psychotic symptoms associated with posttraumatic stress disorder may be a reasonable indication for antipsychotic use, but more research is needed.

Autism: Improving behavioral symptoms

Pharmacotherapy for children with autism and pervasive developmental disorders (PDD) generally targets aggression, irritability, stereotypic behavior, hyperactivity, self-abusive behavior, and self-stimulatory behavior. Almost all classes of psychotropics—including antipsychotics, selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, mood stabilizers, and anxiolytics—have been tested in clinical trials, with varying degrees of success.

Haloperidol has been shown to improve behavioral symptoms, including educational learning.⁶ Dyskinesias—including tardive dyskinesia—remain a concern, however, with long-term use of haloperidol in children.

Recently, attention has turned to atypical antipsychotics, with their lower risk of extrapyramidal symptoms (EPS). Double-blind, placebo-controlled studies have demonstrated the efficacy of these agents in treating autistic and developmental disorders; risperidone and olanzapine have been studied most extensively.

Risperidone. A 16-week open-label trial of 24 children ages 3 to 6 with autistic disorders demonstrated modest improvement with risperidone, 0.5 mg/d. At least 25% improvement was seen in:

 

• the Children’s Psychiatric Rating Scale (CPRS)
• hyperactivity, fidgetiness, rhythmic motions, mood lability, and angry affect, as measured by the Childhood Autism Rating Scale (CARS)
• functional impairment, as determined by the Children’s Global Assessment Scale (C-GAS).

Overall, risperidone was well-tolerated at this low dosage, although two children did not complete the study because of side effects. Three children gained more than 10% of their body weight.⁷

In a 12-month semi-naturalistic prospective study, 11 children and adolescents ages 7 to 17 (mean age 12.3) with autism (n=9) or PDD (n=2) were treated with risperidone. Starting dosage was 0.5 mg/d, mean dosage was 2.7 mg/d, and maximum dosage was 6 mg/d (0.1/mg/kg/d). Behavioral symptoms improved significantly with risperidone in 10 of the 11 subjects during the first 6 months of treatment. Autism’s core symptoms were also mildly improved, although more slowly and later in treatment. Risperidone continued to work in patients treated for 12 months, whereas behavioral symptoms reemerged in those who discontinued drug therapy after 6 months. Weight gain was the most common side effect.

After 6 months of therapy two patients developed facial dystonia, which resolved after the risperidone dosage was reduced or discontinued. Amenorrhea was observed in one patient, but no changes were reported in liver function, blood tests, or electrocardiogram (ECG) readings.⁸

Box 2

Others have contributed greatly to our understanding of using atypicals in treating autism and PDD.^9,10 Posey et al reported using risperidone to treat two boys, ages 23 months and 29 months. In both cases, aggression was reduced and social relatedness improved significantly. One patient’s treatment was complicated by dose-related presistent tachycardia and QTc prolongation.⁹

McDougle conducted an initial prospective, 12-week, open-label study examining risperidone treatment in 18 children and adolescents (15 boys and 3 girls, mean age 10) with PDD,¹⁰ followed by an 8-week, double-blind, placebo-controlled study of risperidone in 100 children with autistic disorders (excluding Asperger’s disorder).¹¹ Mean dosage was 2.1 mg/d (0.75 mg to 3.5 mg/d) divided into two doses. The study examined the benefit in a relatively young cohort (Tanner stages I and II—children who have yet to complete sexual development).

After 2 to 4 weeks of treatment, irritability improved most significantly (>25% improvement on the Aberrant Behavior Checklist), and stereotypic behavior also improved. Inappropriate speech patterns did not change. Anecdotal reports suggested that social relatedness improved, although quantitative evaluation was inconclusive. EPS, as measured by the Simpson Angus EPS score, were mild and generally seen in early treatment. Side effects included increased appetite, weight gain, decreased energy, and sedation.¹¹

Olanzapine. Most studies of olanzapine in children and adolescents with autistic disorders have been open-label:

Eight patients (four adults, ages 18 to 42, and four children, ages 5 to 17) were treated with olanzapine, mean dosage 7.8 mg/d for 12 weeks. Seven completed the study, and six were rated “much improved” or “very much improved” on the global improvement item of the Clinical Global Impression (CGI) scale. Hyperactivity, aggression, anger, and self-injurious behavior improved significantly, as did social relatedness, affectual reactions, sensory responses, and language use. The drug was well tolerated, with the most significant side effect being increased appetite and weight gain (mean increase 8.3 kg).¹²

In an open-label pilot study, 12 children with autism (mean age 8) were randomly assigned to 6 weeks of treatment with olanzapine (mean final dosage 7.9 mg/d) or haloperidol (mean final dosage 1.4 mg/d). Symptoms were reduced in both groups. Five of six children in the olanzapine group and three of six children in the haloperidol group were noted as responders, according to the CGI improvement item and the Children’s Psychiatric Rating Scale (CPRS) Autism Factor. Drowsiness and weight gain were seen with olanzapine.¹³

Similar results were obtained in another study, with significant improvements in irritability, hyperactivity, and excessive speech, as evaluated by the Aberrant Behavior Checklist.^14,15

Summary. Atypical antipsychotics appear to be effective and well tolerated in children and adolescents with autistic and developmental disorders. Double-blind, placebo-controlled studies confirm the benefit of risperidone; open-label trials likewise suggest the benefit of olanzapine. Research is limited on quetiapine and ziprasidone in this population.

Weight gain appears to be the most problematic side effect and should be monitored. Early dietary education and discussion with the patient, parents, and family can help keep weight gain to a minimum.

 

Tourette’s disorder: Modest benefit

Tourette’s disorder and simple motor or vocal tics have traditionally been treated with the older neuroleptics, particularly haloperidol and pimozide. These agents have fallen out of favor in younger patients, however, because of the risk of short- and long-term side effects, including EPS, tardive dyskinesia, cognitive blunting, and school phobia.

Clinicians have turned to alternate agents, such as clonidine and guanfacine (alpha-2 agonists) to treat tic disorders, and now are trying atypical antipsychotics. In open and controlled studies, the atypicals have demonstrated moderate improvement in Tourette’s disorder. Even so, none of the newer agents has shown benefits comparable to haloperidol, which recently demonstrated 66% improvement in tic symptoms when compared with a placebo.¹⁶ For example:

• ziprasidone—35% improvement in tic symptoms when compared with a placebo¹⁷
• risperidone—44% improvement when compared with a placebo in 17 pediatric patients¹⁸
• clozapine—no effect on tic symptoms¹⁶ (clozapine causes little or no dopamine [D2] blockade, which most likely explains this result)
• olanzapine—modest to moderate benefit, but somewhat less effective than risperidone or ziprasidone (small sample size and inclusion of adult patients have confounded interpretation in the studies examining response to risperidone and olanzapine).^16,17

Sedation was the most common side effect seen with use of risperidone, ziprasidone, or olanzapine, and weight gain was particularly problematic with olanzapine.¹⁶ No ECG abnormalities were noted in the 28 children treated with ziprasidone.¹⁷

Disruptive behavior: Improved conduct

The disruptive behavior disorders of childhood and adolescence include conduct disorder and oppositional defiant disorder. The only two antipsychotic medications approved to treat behavioral symptoms are chlorpromazine and thioridazine. These indications were approved in the 1980s, based on limited trials with poor statistical comparison and controlled study groups. Moreover, thioridazine has since been issued a black-box warning because of concerns about cardiac complications from QTc prolongation.

Among the typical antipsychotics, haloperidol has been studied the most extensively in disruptive behavior disorders, although it is not FDA-approved for this indication. Haloperidol has decreased destructive and aggressive behavior, oppositionality, and hostility, and has improved scores on children’s psychiatric and CGI scales.¹⁹

More recent studies have examined the role of atypical antipsychotics in disruptive behavior disorders, primarily risperidone.

Risperidone. In a double-blind, placebo-controlled study, use of risperidone (average dosage 0.75 to 1.50 mg/d) improved aggression and delinquent behavior in 20 children, ages 5 to 15, diagnosed with conduct disorder.²⁰ In a larger 6-week, multisite, double-blind, placebo-controlled study, researchers examined the use of risperidone (mean dosage 1.11 mg/kg/d) in 118 children with conduct problems and borderline intellectual functioning (60% had oppositional defiant disorder, 40% had conduct disorder, and 60% had ADHD). Behaviors—anxious, hyperactive, self-injurious, isolative, and stereotypic—improved, as did adaptive skills. The most common side effects were sedation, GI distress, weight gain, hyperprolactinemia, rhinitis, and headaches.²¹ Replication of this study produced similar findings.²²

In an extension study of conduct disorder, 34 children ages 5 to 14 with comorbid borderline intellectual functioning were treated for approximately 1 year with risperidone (mean dosage 1.48 mg/d). Clinical benefit, defined by statistically significant improvement in the conduct problem subscale of the Nisonger Child Behavior Rating Form, was noted throughout the study. Prolactin levels were elevated after 3 months of treatment but declined thereafter.²³

No controlled studies have been published using olanzapine in children and adolescents with disruptive behavior disorders. As other medications—lithium, anticonvulsants, and psychostimulants—are available for symptomatic treatment of this population, questions remain. Are antipsychotics the best class of medication for this purpose, and should they be tried as first-line therapy? Few studies have compared the efficacy of antipsychotics and other pharmacologic options.

Summary

Pharmacotherapy of childhood psychiatric conditions is complex and an extremely underdeveloped area of research. Even so, clinicians are experimenting with the use of atypical antipsychotics on a trial-and-error basis or as adjuncts to other medications for childhood conditions beyond schizophrenia.²⁴

Even more than in adult populations, judicious use of atypical antipsychotics is warranted in children and adolescents because of potential long-term consequences. The risk of interfering with normal development and the unique pharmacokinetics of childhood are important considerations. At the same time, atypical antipsychotics may offer the potential to improve behavior and function in children with intractable psychiatric conditions.

Related resources

• Pappadopulas E, Jensen PS, Schur SB, et al. Real world atypical antipsychotic prescribing practices in public child and adolescent inpatient settings. Schizophr Bull 2002;28(1):111-121.
• Malone RP, Sheikh R, Zito JM. Novel antipsychotic medications is the treatment of children and adolescents. Psychiatr Serv 1999; 50(2):171-174.

Drug brand names

• Chlorpromazine • Thorazine
• Clonidine • Catapres
• Clozapine • Clozaril
• Guanfacine • Tenex
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

 

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Prescribing of atypical antipsychotics for children and adolescents is increasing, despite a lack of randomized controlled clinical trials. Like many psychiatrists, you may be treating pediatric patients with these medications for a variety of indications beyond psychosis.

Three factors are driving the use of atypical antipsychotics for broader indications:

• substantial evidence that these newer agents are safer and more effective than typical antipsychotics¹
  
• inadequate response of childhood and adolescent psychiatric disorders to their primary treatments
  
• evidence that atypical antipsychotics have potential thymoleptic, antiaggressive, and anxiolytic properties.
  

These attributes already have expanded atypical antipsychotic use in adult patients. In fact, atypicals are being used more extensively in adults for affective and nonpsychotic conditions than for schizophrenia.²

In preparing the following two-part article for Current Psychiatry, we scoured the available literature—Medline, abstracts from scientific meetings, and American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters—to examine the evolving role of atypical antipsychotics in children and adolescents. In part 1 of this article, we discuss using atypicals in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. In part 2, we look at evidence for using atypicals in children with autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa, anxiety disorders, and stuttering.

Box 1

Shift in pharmacotherapy of schizophrenia.

One-quarter of patients with schizophrenia develop the disorder before age 15, and subtle psychotic manifestations are often observed in early childhood.³ In general, schizophrenia’s presenting symptoms are comparable in adults and children, but the childhood/adolescent-onset form is more severe.^4,5

During the past 5 years, pharmacotherapy of adult schizophrenia has shifted dramatically away from typical antipsychotics. Atypical agents have shown greater efficacy and tolerability, especially with respect to extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).¹

In a recent survey, most general and specialist psychiatrists (86%) said they prefer using atypical antipsychotics as first-line treatment for new-onset schizophrenia and as maintenance therapy. They also reported using atypicals to treat patients with dementia (80%), personality disorders (69%), developmental delay/mental retardation (65%), and autism (40%).⁶

Translating adult findings to children. Most evidence of atypical antipsychotics’ efficacy and tolerability is derived from adult studies, which likely will continue to influence clinical practice more than the limited number of child and adolescent studies. In 1998, a thorough review of atypical antipsychotic use in child and adolescent psychiatry found only five blinded placebo-controlled clinical trials, 24 open-label trials, and 33 case series.⁷ A follow-up review in 1999 again found mainly case reports and case series, with a handful of controlled studies.⁸

Available atypical antipsychotics include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. An investigational agent—aripiprazole—is likely to be available soon for clinical use.

Issues in pediatric use of atypicals

When prescribing atypical antipsychotics, it is important to balance the benefit of treatment with the risk of exposing children to possible adverse effects. Side effects associated with atypicals include weight gain, secondary metabolic disturbances such as hyperglycemia, hyperprolactinemia, and cardiac conduction abnormalities. These side effects are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to antipsychotics.

Weight gain. Younger patients may be particularly susceptible to weight gain with the use of the atypicals. In a state hospital adult population, Buckley et al found a strong inverse relationship between patient age and weight gain associated with atypical antipsychotic use.⁹ Key issues for pediatric populations are:

• Will children have difficulties losing weight over time?
  
• Will they stop their medications over time?
  
• Will they stop their medications because of this effect?
  
• Will they be further stigmatized at school because of obesity?
  
• Are they at increased risk to develop diabetes mellitus?
  
• What are the long-term consequences of antipsychotic-induced obesity and metabolic disturbances for this patient population?
  

 

Hyperprolactinemia in children and adolescents may lead to breast enlargement and galactorrhea, which are particularly distressing in this age group. Sustained elevation of prolactin may affect the regulation of other hormones, resulting in low estrogen and testosterone levels. The long-term impact of these changes on adolescent growth and development is unknown. Antipsychotic-induced hyperprolactinemia also may be associated with reduced bone density.¹⁰

Abnormal cardiac conduction. Thioridazine recently received a “black box” label warning from the FDA because of sudden deaths and a prolonged QTc interval seen on electrocardiogram (ECG) readings. Several other antipsychotics also show ECG evidence of QTc prolongation.¹¹ However, the clinical significance of this finding is unclear.

Box 2

Table

SUGGESTED DOSAGES OF ATYPICAL ANTIPSYCHOTICS

Drug	FDA-approved dosages for psychosis in adults	For psychosis in children and adolescents	For bipolar disorder in children and adolescents
Clozapine	Initial: 25 mg bid; increase gradually to 300 to 800 mg/d in divided doses	Not recommended for children under age 16 Initial: 12.5 to 25 mg bid; increase gradually to 300 to 450 mg/d (divided) Increased risk of seizures; potential for agranulocytosis	Limited research
Olanzapine	Psychosis. Initial: 5 to 10 mg qd or 5 mg bid; increase to 20 mg qd or 10 mg bid Bipolar disorder. Similar initial; lower maintenance (10 to 20 mg qd or 10 mg bid can often be obtained)	Clinical benefit in children age 10 at 2.5 to 10 mg/d; For age >10, 5 to 20 mg qd or 10 mg bid may be used Sedation and weight gain are common side effects	Clinically beneficial at dosages comparable to those used in psychosis Maintenance dosage may be lower than that required in a primary psychotic disorder
Quetiapine	Initial: 25 mg bid; increase to 300 to 800 mg/d divided in two to three doses	Initial: 12.5 mg bid (50 kg) Maintenance: 50 mg bid (50 kg) Few controlled trials in children	Limited research
Risperidone	Initial: 2 mg/d; may be increased to 4 to 6 mg/d in divided doses	Clinical trials indicate benefit at 0.25 to 0.5 mg qd or bid May be increased as needed to 0.5 to 1.5 mg/d in single or divided doses	Clinically beneficial at dosages comparable to those used in psychosis
Ziprasidone	Initial: 20 to 40 mg bid; may be increased to 40 to 80 mg bid	Preliminary studies suggest benefit at 10 to 20 mg bid, increasing to 20 to 60 mg bid Not recommended as first-line therapy in this population	Limited research
* The FDA has not approved a specific indication for these agents for use in children and adolescents. In adult patients, atypical antipsychotics have been approved for psychosis, and olanzapine is FDA-approved for psychosis and mood disorders.

 

Special care is required to decrease the risks associated with using antipsychotics in children and adolescents and to increase compliance with medication recommendations (Box 1).

Pharmacokinetics in children and adolescents

Administering medications to children and adolescents requires special precautions. Younger patients respond differently than adults to psychotropic medications because of differences in pharmacokinetics—how the body handles a drug—and pharmacodynamics—the drug’s effect on the body.

During a child’s growth and development, physiologic changes in absorption, distribution, metabolism, and excretion may affect drug delivery to target tissue (Box 2).^12,13 Maturation of brain regions and neurotransmitter systems also may alter a medication’s effect at different ages.

Antipsychotic dosage recommendations and therapeutic ranges for children and adolescents have been published but are extrapolated from adult studies because studies in children are lacking. There is danger, however, in using body weight and proportionately reducing an adult dosage to obtain a pediatric dosage. The plasma concentration may ultimately be subtherapeutic or toxic.¹⁴

The liver metabolizes most antipsychotics. The higher rate of hepatic metabolism in children would suggest that on a milligram-to-kilogram basis a child or adolescent would need a higher dose. Children, however, require smaller weight-adjusted doses of antipsychotics than do adults to achieve the same therapeutic effect.¹⁵ Children have a greater density of dopamine D-1 and D-2 receptors than do adults, suggesting a greater sensitivity to the beneficial and adverse effects of antipsychotics. To date, dopamine receptor occupancy in children/adolescents with schizophrenia has not been studied with positron emission tomography.

Summary. Compared with adults, children require a reduced milligram-to-kilogram dosage of antipsychotics to achieve the same therapeutic effect and avoid unwanted side effects. Children younger than age 10 or weighing less than 50 kg typically should start with the lowest starting dose, given once or twice a day (Table). The dose should be slowly increased based on the presence of side effects and remission of symptoms.

Maximum daily dosages for children weighing less than 50 kg should rarely exceed one-half of an adult antipsychotic dosage, particularly when used for symptoms of disorders other than primary psychosis. However, dosages closer to those used in adults may be necessary when treating primary psychosis in early-onset schizophrenia, especially in an adolescent (Box 3).

Box 3

Childhood/adolescent-onset schizophrenia

Typical antipsychotics appear to have limited efficacy in childhood/adolescent-onset schizophrenia, based on a small number of available case series and relatively short open-label trials.¹⁶ In a single-arm, placebo-controlled trial, haloperidol was effective in 16 children ages 5 to 12, but its use was associated with substantial EPS. A similar intolerance was demonstrated in a comparative trial of thioridazine and thiothixene.

Less is known about the incidence of tardive dyskinesia, but there is no reason to believe that the rate is lower in children and adolescents than in adults with schizophrenia (estimated at 5% per year for the first 5 years of treatment).

Clozapine. Information is emerging on the efficacy and tolerability of atypical antipsychotics in childhood/adolescent-onset schizophrenia.¹⁶ Clozapine has been studied more than other atypicals, in part because of the severity of early-onset schizophrenia and because clozapine has been used in clinical practice longer than the other agents in that class.

Early case reports and small open-labeled trials confirmed that clozapine was effective for children and adolescents with schizophrenia who had failed prior antipsychotic treatments.^17-19 A randomized, double-blind, controlled trial from the childhood schizophrenia division of the National Institute of Mental Health provided the most reliable information.¹⁷ In that 6-week treatment study, 21 severely ill adolescents (mean age 14) received clozapine, mean dosage 176 mg/d, or haloperidol, mean dosage 16 mg/d. Response to clozapine was greater for both positive and negative symptoms, and the difference was clinically and statistically significant. In addition, 62% of clozapine-treated patients were rated very much improved on the Clinical Global Impression (CGI) scale.

In the same trial, clozapine treatment was complicated by higher rates of adverse effects than are typically observed in adult studies:

 

• Sedation was reported in 90% of patients.
  
• 2 of 10 patients had a seizure during clozapine therapy.
  
• A 2% rate of agranulocytosis was disconcerting, given the lower adult rate (0.38%) and the brevity of the trial. As older age is a known risk factor for clozapine-induced agranulocytosis, it may be that children and the elderly are more susceptible to this side effect.
  

Risperidone. Most of the information on risperidone therapy in childhood/adolescent-onset schizophrenia is derived from small case series,⁷ which confirm its efficacy for both positive and negative symptoms. Recently, low-dose risperidone (less than 1.5 mg/d) was shown to be effective in young patients with schizophrenia’s prodrome.²⁰ In general, risperidone dosages of 1 to 2 mg/d are appropriate for patients with childhood/adolescent-onset schizophrenia. Children have been observed to be particularly sensitive to the drug’s EPS and prolactin-elevating effects.

Olanzapine has been effective in this patient population at dosages up to 10 mg/d.^7,16,21 In a pilot study, Kumra et al administered olanzapine to 23 children with schizophrenia who had not previously responded to neuroleptic treatment. After 8 weeks, the children improved on the Brief Psychiatric Rating Scale, the Scale for the Assessment for Negative Symptoms, and the Scale for the Assessment of Positive Symptoms.²¹

Similarities and differences in olanzapine’s side effects in adults and children/adolescents with schizophrenia were seen in a recent study. Children had more weight gain, sedation, and dystonia, whereas adults had significantly more cardiac arrhythmias.²²

Quetiapine. McConville and colleagues examined the efficacy and tolerability of quetiapine in 10 adolescents with chronic psychosis (7 with schizoaffective disorder and 3 with bipolar disorder). In this 3-week study, quetiapine was well-tolerated; in several patients, dosages exceeded 750 mg/d. Psychotic symptoms were reduced, and there was global improvement in functioning.²³

Other antipsychotics. There are no published data on the use of ziprasidone or aripiprazole in childhood/adolescent-onset schizophrenia.

Comparative data are very limited. One retrospective analysis compared the tolerability of risperidone, olanzapine, and quetiapine in 116 adolescent patients.²⁴ Over 3 months, 75 patients received risperidone (mean 2.6 mg/d), 16 received olanzapine (mean 13.3 mg/d), and 25 were treated with quetiapine (mean 210.3 mg/d). Weight gain was the most common side effect; patients gained an average 8.6 lb with risperidone, 7.2 lb with quetiapine, and 14.1 lb with olanzapine. EPS were treated in seven (10%) patients taking risperidone, four (25%) taking olanzapine, and no patients taking quetiapine.

Bipolar disorder

As in the adult population, there has been substantial use of antipsychotics in children and adolescents with bipolar illness. Bipolar I disorder affects an estimated 0.6% of adolescents and is even being diagnosed in prepubertal patients.

Lithium, valproate, carbamazapine, and adjunctive treatment with benzodiazapines traditionally have been used to treat bipolar I disorders. Although practice guidelines recommend lithium and divalproex sodium as first-line treatments for bipolar illness, these recommendations are generally based on a preference for first-line agents that have potential use in maintenance treatment. The benefit of medications in bipolar disorder, however, is two-fold:

• Initial pharmacotherapy is usually instituted to target manic or mixed symptoms, and continued treatment is necessary to avoid relapse. The new antipsychotics—particularly risperidone, olanzapine, and quetiapine—are beneficial to treat agitated mania and disrupted sleep that may impair function and/or mandate inpatient stabilization. The highly sedative properties offer an acute benefit in restoring disrupted sleep.
  
• Psychotic symptoms seen in mania may need to be targeted independent of the mood symptoms and would thus suggest the use of an antipsychotic. In early-onset bipolar disorder, antipsychotics are used primarily as adjuncts to mood stabilizers.
  

Evidence. The 1997 AACAP practice parameters on treating bipolar disorders included limited information on the use of antipsychotics. No studies had examined the efficacy of neuroleptics (i.e., haloperidol) in children and adolescents, and only one case study had been published on the benefit on a newer antipsychotic agent.²⁵ Since then, case reports and open studies have contributed to our understanding of the role the newer antipsychotics may play in treating this disorder:

• In the 1994 case report, an adolescent with bipolar disorder showed benefit when treated with clozapine.²⁶
  
• In a retrospective chart review, 28 children ages 4 to 17 with bipolar disorder (25 mixed and 3 hypomanic) were treated with adjunctive risperidone for 6 months. Most (82%) showed significant improvement in mania and aggression on a mean dosage of 1.7 +/- 1.3 mg/d. Attention-deficit/hyperactivity disorder symptoms improved in 8% of the patients.²⁷
  
• Affective symptoms (predominantly suggestive of bipolar disorder), aggression, and violent behavior in 11 children and adolescents ages 5 to 16 showed therapeutic response to an open trial of adjunctive low-dose (0.75 to 2.5 mg/d) risperidone.²⁸
  

 

Olanzapine. Recent interest in olanzapine’s thymoleptic propertities has contributed to its clinical use in bipolar disorder, specifically in psychotic mania. Olanzapine has also been studied as long-term maintenance therapy in bipolar disorder. In a 47-week study, adult patients receiving olanzapine improved significantly more than those receiving valproate (47% vs. 34% by the Young Mania Rating Scale) after 3 weeks. Both medications were effective throughout the long-term, randomized, double-blind study.²⁹

Two case series and one open trial have examined olanzapine as primary or adjunctive treatment for children and adolescents with bipolar disorder. In the open study, Frazier and colleagues gave olanzapine, 2.5 to 20 mg/d, to 23 children ages 5 to 14.³⁰ After 8 weeks, the response rate was 61% (defined as 30% or greater improvement on the Young Mania Rating Scale). Weight gain was the predominant side effect (mean increase 5 kg).

Chang and colleagues demonstrated “marked improvement” in CGI scores when using olanzapine as adjunctive therapy for three youths with bipolar disorder.³¹ Similar findings were reported when treating seven youths with acute mania.³² Olanzapine’s broad affinity for dopaminergic and serotonergic receptors may explain these positive outcomes.

Other atypicals. No studies have been published on the use of quetiapine, ziprasidone, or aripiprazole in childhood mood disorders.

Psychotic depression

Psychosis can complicate depression in adults and adolescents. In a small study of adolescents with psychotic depression, Gellar et al demonstrated conventional neuroleptics’ benefit in combination with antidepressants.³³ We have no data, however, on use of atypicals in childhood depression, and published accounts of depression in bipolar patients treated with atypicals are of some concern.

In one study,³⁴ four of six patients with bipolar disorder developed dysphoric mood within 3 months of starting risperidone. Two met the criteria for major depression and required antidepressant therapy. This finding was somewhat surprising, given risperidone’s antidepressant benefit in some adults, most likely due to its 5-HT2 antagonistic effect. Frazier and colleagues similiarly noted that one patient discontinued treatment during an open-label trial examining the benefit of olanzapine in juvenile bipolar disorder.³⁰

These findings in the adolescent bipolar population should not be ignored when you consider treating a primary depressive disorder with psychosis. Antipsychotics certainly can be useful for treating psychotic depression, especially acutely for stabilization and preventing harm to self. Atypical antipsychotics have consistently been proven to have less adverse side effects than typical antipsychotics and thus would be preferred in children and adolescents. Research is needed to examine possible worsening of dysphoria.

Related resources

• Hermann RC, Yang D, Ettner SL, et al. Prescription of antipsychotic drugs by office-based physicians in the United States, 1989-1997. Psychiatric Services 2002;53:425-30.
  
• Stigler KA, Potenza MN, McDougle CJ. Tolerability profile of atypical antipsychotics in children and adolescents (review). Paediatric Drugs 2001;3(12):927-94
  
• American Academy of Child and Adolescent Psychiatry http://www.aacap.org
  

Drug brand names

• Clozapine • Clozaril
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  
• Aripiprazole (investigational)
  

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Prescribing of atypical antipsychotics for children and adolescents is increasing, despite a lack of randomized controlled clinical trials. Like many psychiatrists, you may be treating pediatric patients with these medications for a variety of indications beyond psychosis.

Three factors are driving the use of atypical antipsychotics for broader indications:

• substantial evidence that these newer agents are safer and more effective than typical antipsychotics¹
  
• inadequate response of childhood and adolescent psychiatric disorders to their primary treatments
  
• evidence that atypical antipsychotics have potential thymoleptic, antiaggressive, and anxiolytic properties.
  

These attributes already have expanded atypical antipsychotic use in adult patients. In fact, atypicals are being used more extensively in adults for affective and nonpsychotic conditions than for schizophrenia.²

In preparing the following two-part article for Current Psychiatry, we scoured the available literature—Medline, abstracts from scientific meetings, and American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters—to examine the evolving role of atypical antipsychotics in children and adolescents. In part 1 of this article, we discuss using atypicals in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. In part 2, we look at evidence for using atypicals in children with autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa, anxiety disorders, and stuttering.

Box 1

Shift in pharmacotherapy of schizophrenia.

One-quarter of patients with schizophrenia develop the disorder before age 15, and subtle psychotic manifestations are often observed in early childhood.³ In general, schizophrenia’s presenting symptoms are comparable in adults and children, but the childhood/adolescent-onset form is more severe.^4,5

During the past 5 years, pharmacotherapy of adult schizophrenia has shifted dramatically away from typical antipsychotics. Atypical agents have shown greater efficacy and tolerability, especially with respect to extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).¹

In a recent survey, most general and specialist psychiatrists (86%) said they prefer using atypical antipsychotics as first-line treatment for new-onset schizophrenia and as maintenance therapy. They also reported using atypicals to treat patients with dementia (80%), personality disorders (69%), developmental delay/mental retardation (65%), and autism (40%).⁶

Translating adult findings to children. Most evidence of atypical antipsychotics’ efficacy and tolerability is derived from adult studies, which likely will continue to influence clinical practice more than the limited number of child and adolescent studies. In 1998, a thorough review of atypical antipsychotic use in child and adolescent psychiatry found only five blinded placebo-controlled clinical trials, 24 open-label trials, and 33 case series.⁷ A follow-up review in 1999 again found mainly case reports and case series, with a handful of controlled studies.⁸

Available atypical antipsychotics include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. An investigational agent—aripiprazole—is likely to be available soon for clinical use.

Issues in pediatric use of atypicals

When prescribing atypical antipsychotics, it is important to balance the benefit of treatment with the risk of exposing children to possible adverse effects. Side effects associated with atypicals include weight gain, secondary metabolic disturbances such as hyperglycemia, hyperprolactinemia, and cardiac conduction abnormalities. These side effects are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to antipsychotics.

Weight gain. Younger patients may be particularly susceptible to weight gain with the use of the atypicals. In a state hospital adult population, Buckley et al found a strong inverse relationship between patient age and weight gain associated with atypical antipsychotic use.⁹ Key issues for pediatric populations are:

• Will children have difficulties losing weight over time?
  
• Will they stop their medications over time?
  
• Will they stop their medications because of this effect?
  
• Will they be further stigmatized at school because of obesity?
  
• Are they at increased risk to develop diabetes mellitus?
  
• What are the long-term consequences of antipsychotic-induced obesity and metabolic disturbances for this patient population?
  

 

Hyperprolactinemia in children and adolescents may lead to breast enlargement and galactorrhea, which are particularly distressing in this age group. Sustained elevation of prolactin may affect the regulation of other hormones, resulting in low estrogen and testosterone levels. The long-term impact of these changes on adolescent growth and development is unknown. Antipsychotic-induced hyperprolactinemia also may be associated with reduced bone density.¹⁰

Abnormal cardiac conduction. Thioridazine recently received a “black box” label warning from the FDA because of sudden deaths and a prolonged QTc interval seen on electrocardiogram (ECG) readings. Several other antipsychotics also show ECG evidence of QTc prolongation.¹¹ However, the clinical significance of this finding is unclear.

Box 2

Table

SUGGESTED DOSAGES OF ATYPICAL ANTIPSYCHOTICS

Drug	FDA-approved dosages for psychosis in adults	For psychosis in children and adolescents	For bipolar disorder in children and adolescents
Clozapine	Initial: 25 mg bid; increase gradually to 300 to 800 mg/d in divided doses	Not recommended for children under age 16 Initial: 12.5 to 25 mg bid; increase gradually to 300 to 450 mg/d (divided) Increased risk of seizures; potential for agranulocytosis	Limited research
Olanzapine	Psychosis. Initial: 5 to 10 mg qd or 5 mg bid; increase to 20 mg qd or 10 mg bid Bipolar disorder. Similar initial; lower maintenance (10 to 20 mg qd or 10 mg bid can often be obtained)	Clinical benefit in children age 10 at 2.5 to 10 mg/d; For age >10, 5 to 20 mg qd or 10 mg bid may be used Sedation and weight gain are common side effects	Clinically beneficial at dosages comparable to those used in psychosis Maintenance dosage may be lower than that required in a primary psychotic disorder
Quetiapine	Initial: 25 mg bid; increase to 300 to 800 mg/d divided in two to three doses	Initial: 12.5 mg bid (50 kg) Maintenance: 50 mg bid (50 kg) Few controlled trials in children	Limited research
Risperidone	Initial: 2 mg/d; may be increased to 4 to 6 mg/d in divided doses	Clinical trials indicate benefit at 0.25 to 0.5 mg qd or bid May be increased as needed to 0.5 to 1.5 mg/d in single or divided doses	Clinically beneficial at dosages comparable to those used in psychosis
Ziprasidone	Initial: 20 to 40 mg bid; may be increased to 40 to 80 mg bid	Preliminary studies suggest benefit at 10 to 20 mg bid, increasing to 20 to 60 mg bid Not recommended as first-line therapy in this population	Limited research
* The FDA has not approved a specific indication for these agents for use in children and adolescents. In adult patients, atypical antipsychotics have been approved for psychosis, and olanzapine is FDA-approved for psychosis and mood disorders.

 

Special care is required to decrease the risks associated with using antipsychotics in children and adolescents and to increase compliance with medication recommendations (Box 1).

Pharmacokinetics in children and adolescents

Administering medications to children and adolescents requires special precautions. Younger patients respond differently than adults to psychotropic medications because of differences in pharmacokinetics—how the body handles a drug—and pharmacodynamics—the drug’s effect on the body.

During a child’s growth and development, physiologic changes in absorption, distribution, metabolism, and excretion may affect drug delivery to target tissue (Box 2).^12,13 Maturation of brain regions and neurotransmitter systems also may alter a medication’s effect at different ages.

Antipsychotic dosage recommendations and therapeutic ranges for children and adolescents have been published but are extrapolated from adult studies because studies in children are lacking. There is danger, however, in using body weight and proportionately reducing an adult dosage to obtain a pediatric dosage. The plasma concentration may ultimately be subtherapeutic or toxic.¹⁴

The liver metabolizes most antipsychotics. The higher rate of hepatic metabolism in children would suggest that on a milligram-to-kilogram basis a child or adolescent would need a higher dose. Children, however, require smaller weight-adjusted doses of antipsychotics than do adults to achieve the same therapeutic effect.¹⁵ Children have a greater density of dopamine D-1 and D-2 receptors than do adults, suggesting a greater sensitivity to the beneficial and adverse effects of antipsychotics. To date, dopamine receptor occupancy in children/adolescents with schizophrenia has not been studied with positron emission tomography.

Summary. Compared with adults, children require a reduced milligram-to-kilogram dosage of antipsychotics to achieve the same therapeutic effect and avoid unwanted side effects. Children younger than age 10 or weighing less than 50 kg typically should start with the lowest starting dose, given once or twice a day (Table). The dose should be slowly increased based on the presence of side effects and remission of symptoms.

Maximum daily dosages for children weighing less than 50 kg should rarely exceed one-half of an adult antipsychotic dosage, particularly when used for symptoms of disorders other than primary psychosis. However, dosages closer to those used in adults may be necessary when treating primary psychosis in early-onset schizophrenia, especially in an adolescent (Box 3).

Box 3

Childhood/adolescent-onset schizophrenia

Typical antipsychotics appear to have limited efficacy in childhood/adolescent-onset schizophrenia, based on a small number of available case series and relatively short open-label trials.¹⁶ In a single-arm, placebo-controlled trial, haloperidol was effective in 16 children ages 5 to 12, but its use was associated with substantial EPS. A similar intolerance was demonstrated in a comparative trial of thioridazine and thiothixene.

Less is known about the incidence of tardive dyskinesia, but there is no reason to believe that the rate is lower in children and adolescents than in adults with schizophrenia (estimated at 5% per year for the first 5 years of treatment).

Clozapine. Information is emerging on the efficacy and tolerability of atypical antipsychotics in childhood/adolescent-onset schizophrenia.¹⁶ Clozapine has been studied more than other atypicals, in part because of the severity of early-onset schizophrenia and because clozapine has been used in clinical practice longer than the other agents in that class.

Early case reports and small open-labeled trials confirmed that clozapine was effective for children and adolescents with schizophrenia who had failed prior antipsychotic treatments.^17-19 A randomized, double-blind, controlled trial from the childhood schizophrenia division of the National Institute of Mental Health provided the most reliable information.¹⁷ In that 6-week treatment study, 21 severely ill adolescents (mean age 14) received clozapine, mean dosage 176 mg/d, or haloperidol, mean dosage 16 mg/d. Response to clozapine was greater for both positive and negative symptoms, and the difference was clinically and statistically significant. In addition, 62% of clozapine-treated patients were rated very much improved on the Clinical Global Impression (CGI) scale.

In the same trial, clozapine treatment was complicated by higher rates of adverse effects than are typically observed in adult studies:

 

• Sedation was reported in 90% of patients.
  
• 2 of 10 patients had a seizure during clozapine therapy.
  
• A 2% rate of agranulocytosis was disconcerting, given the lower adult rate (0.38%) and the brevity of the trial. As older age is a known risk factor for clozapine-induced agranulocytosis, it may be that children and the elderly are more susceptible to this side effect.
  

Risperidone. Most of the information on risperidone therapy in childhood/adolescent-onset schizophrenia is derived from small case series,⁷ which confirm its efficacy for both positive and negative symptoms. Recently, low-dose risperidone (less than 1.5 mg/d) was shown to be effective in young patients with schizophrenia’s prodrome.²⁰ In general, risperidone dosages of 1 to 2 mg/d are appropriate for patients with childhood/adolescent-onset schizophrenia. Children have been observed to be particularly sensitive to the drug’s EPS and prolactin-elevating effects.

Olanzapine has been effective in this patient population at dosages up to 10 mg/d.^7,16,21 In a pilot study, Kumra et al administered olanzapine to 23 children with schizophrenia who had not previously responded to neuroleptic treatment. After 8 weeks, the children improved on the Brief Psychiatric Rating Scale, the Scale for the Assessment for Negative Symptoms, and the Scale for the Assessment of Positive Symptoms.²¹

Similarities and differences in olanzapine’s side effects in adults and children/adolescents with schizophrenia were seen in a recent study. Children had more weight gain, sedation, and dystonia, whereas adults had significantly more cardiac arrhythmias.²²

Quetiapine. McConville and colleagues examined the efficacy and tolerability of quetiapine in 10 adolescents with chronic psychosis (7 with schizoaffective disorder and 3 with bipolar disorder). In this 3-week study, quetiapine was well-tolerated; in several patients, dosages exceeded 750 mg/d. Psychotic symptoms were reduced, and there was global improvement in functioning.²³

Other antipsychotics. There are no published data on the use of ziprasidone or aripiprazole in childhood/adolescent-onset schizophrenia.

Comparative data are very limited. One retrospective analysis compared the tolerability of risperidone, olanzapine, and quetiapine in 116 adolescent patients.²⁴ Over 3 months, 75 patients received risperidone (mean 2.6 mg/d), 16 received olanzapine (mean 13.3 mg/d), and 25 were treated with quetiapine (mean 210.3 mg/d). Weight gain was the most common side effect; patients gained an average 8.6 lb with risperidone, 7.2 lb with quetiapine, and 14.1 lb with olanzapine. EPS were treated in seven (10%) patients taking risperidone, four (25%) taking olanzapine, and no patients taking quetiapine.

Bipolar disorder

As in the adult population, there has been substantial use of antipsychotics in children and adolescents with bipolar illness. Bipolar I disorder affects an estimated 0.6% of adolescents and is even being diagnosed in prepubertal patients.

Lithium, valproate, carbamazapine, and adjunctive treatment with benzodiazapines traditionally have been used to treat bipolar I disorders. Although practice guidelines recommend lithium and divalproex sodium as first-line treatments for bipolar illness, these recommendations are generally based on a preference for first-line agents that have potential use in maintenance treatment. The benefit of medications in bipolar disorder, however, is two-fold:

• Initial pharmacotherapy is usually instituted to target manic or mixed symptoms, and continued treatment is necessary to avoid relapse. The new antipsychotics—particularly risperidone, olanzapine, and quetiapine—are beneficial to treat agitated mania and disrupted sleep that may impair function and/or mandate inpatient stabilization. The highly sedative properties offer an acute benefit in restoring disrupted sleep.
  
• Psychotic symptoms seen in mania may need to be targeted independent of the mood symptoms and would thus suggest the use of an antipsychotic. In early-onset bipolar disorder, antipsychotics are used primarily as adjuncts to mood stabilizers.
  

Evidence. The 1997 AACAP practice parameters on treating bipolar disorders included limited information on the use of antipsychotics. No studies had examined the efficacy of neuroleptics (i.e., haloperidol) in children and adolescents, and only one case study had been published on the benefit on a newer antipsychotic agent.²⁵ Since then, case reports and open studies have contributed to our understanding of the role the newer antipsychotics may play in treating this disorder:

• In the 1994 case report, an adolescent with bipolar disorder showed benefit when treated with clozapine.²⁶
  
• In a retrospective chart review, 28 children ages 4 to 17 with bipolar disorder (25 mixed and 3 hypomanic) were treated with adjunctive risperidone for 6 months. Most (82%) showed significant improvement in mania and aggression on a mean dosage of 1.7 +/- 1.3 mg/d. Attention-deficit/hyperactivity disorder symptoms improved in 8% of the patients.²⁷
  
• Affective symptoms (predominantly suggestive of bipolar disorder), aggression, and violent behavior in 11 children and adolescents ages 5 to 16 showed therapeutic response to an open trial of adjunctive low-dose (0.75 to 2.5 mg/d) risperidone.²⁸
  

 

Olanzapine. Recent interest in olanzapine’s thymoleptic propertities has contributed to its clinical use in bipolar disorder, specifically in psychotic mania. Olanzapine has also been studied as long-term maintenance therapy in bipolar disorder. In a 47-week study, adult patients receiving olanzapine improved significantly more than those receiving valproate (47% vs. 34% by the Young Mania Rating Scale) after 3 weeks. Both medications were effective throughout the long-term, randomized, double-blind study.²⁹

Two case series and one open trial have examined olanzapine as primary or adjunctive treatment for children and adolescents with bipolar disorder. In the open study, Frazier and colleagues gave olanzapine, 2.5 to 20 mg/d, to 23 children ages 5 to 14.³⁰ After 8 weeks, the response rate was 61% (defined as 30% or greater improvement on the Young Mania Rating Scale). Weight gain was the predominant side effect (mean increase 5 kg).

Chang and colleagues demonstrated “marked improvement” in CGI scores when using olanzapine as adjunctive therapy for three youths with bipolar disorder.³¹ Similar findings were reported when treating seven youths with acute mania.³² Olanzapine’s broad affinity for dopaminergic and serotonergic receptors may explain these positive outcomes.

Other atypicals. No studies have been published on the use of quetiapine, ziprasidone, or aripiprazole in childhood mood disorders.

Psychotic depression

Psychosis can complicate depression in adults and adolescents. In a small study of adolescents with psychotic depression, Gellar et al demonstrated conventional neuroleptics’ benefit in combination with antidepressants.³³ We have no data, however, on use of atypicals in childhood depression, and published accounts of depression in bipolar patients treated with atypicals are of some concern.

In one study,³⁴ four of six patients with bipolar disorder developed dysphoric mood within 3 months of starting risperidone. Two met the criteria for major depression and required antidepressant therapy. This finding was somewhat surprising, given risperidone’s antidepressant benefit in some adults, most likely due to its 5-HT2 antagonistic effect. Frazier and colleagues similiarly noted that one patient discontinued treatment during an open-label trial examining the benefit of olanzapine in juvenile bipolar disorder.³⁰

These findings in the adolescent bipolar population should not be ignored when you consider treating a primary depressive disorder with psychosis. Antipsychotics certainly can be useful for treating psychotic depression, especially acutely for stabilization and preventing harm to self. Atypical antipsychotics have consistently been proven to have less adverse side effects than typical antipsychotics and thus would be preferred in children and adolescents. Research is needed to examine possible worsening of dysphoria.

Related resources

• Hermann RC, Yang D, Ettner SL, et al. Prescription of antipsychotic drugs by office-based physicians in the United States, 1989-1997. Psychiatric Services 2002;53:425-30.
  
• Stigler KA, Potenza MN, McDougle CJ. Tolerability profile of atypical antipsychotics in children and adolescents (review). Paediatric Drugs 2001;3(12):927-94
  
• American Academy of Child and Adolescent Psychiatry http://www.aacap.org
  

Drug brand names

• Clozapine • Clozaril
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  
• Aripiprazole (investigational)
  

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Prescribing of atypical antipsychotics for children and adolescents is increasing, despite a lack of randomized controlled clinical trials. Like many psychiatrists, you may be treating pediatric patients with these medications for a variety of indications beyond psychosis.

Three factors are driving the use of atypical antipsychotics for broader indications:

• substantial evidence that these newer agents are safer and more effective than typical antipsychotics¹
  
• inadequate response of childhood and adolescent psychiatric disorders to their primary treatments
  
• evidence that atypical antipsychotics have potential thymoleptic, antiaggressive, and anxiolytic properties.
  

These attributes already have expanded atypical antipsychotic use in adult patients. In fact, atypicals are being used more extensively in adults for affective and nonpsychotic conditions than for schizophrenia.²

In preparing the following two-part article for Current Psychiatry, we scoured the available literature—Medline, abstracts from scientific meetings, and American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters—to examine the evolving role of atypical antipsychotics in children and adolescents. In part 1 of this article, we discuss using atypicals in childhood/adolescent-onset schizophrenia, bipolar disorder, and psychotic depression. In part 2, we look at evidence for using atypicals in children with autism and developmental disorders, Tourette’s and other tic disorders, disruptive behavior disorders, anorexia nervosa, anxiety disorders, and stuttering.

Box 1

Shift in pharmacotherapy of schizophrenia.

One-quarter of patients with schizophrenia develop the disorder before age 15, and subtle psychotic manifestations are often observed in early childhood.³ In general, schizophrenia’s presenting symptoms are comparable in adults and children, but the childhood/adolescent-onset form is more severe.^4,5

During the past 5 years, pharmacotherapy of adult schizophrenia has shifted dramatically away from typical antipsychotics. Atypical agents have shown greater efficacy and tolerability, especially with respect to extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).¹

In a recent survey, most general and specialist psychiatrists (86%) said they prefer using atypical antipsychotics as first-line treatment for new-onset schizophrenia and as maintenance therapy. They also reported using atypicals to treat patients with dementia (80%), personality disorders (69%), developmental delay/mental retardation (65%), and autism (40%).⁶

Translating adult findings to children. Most evidence of atypical antipsychotics’ efficacy and tolerability is derived from adult studies, which likely will continue to influence clinical practice more than the limited number of child and adolescent studies. In 1998, a thorough review of atypical antipsychotic use in child and adolescent psychiatry found only five blinded placebo-controlled clinical trials, 24 open-label trials, and 33 case series.⁷ A follow-up review in 1999 again found mainly case reports and case series, with a handful of controlled studies.⁸

Available atypical antipsychotics include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. An investigational agent—aripiprazole—is likely to be available soon for clinical use.

Issues in pediatric use of atypicals

When prescribing atypical antipsychotics, it is important to balance the benefit of treatment with the risk of exposing children to possible adverse effects. Side effects associated with atypicals include weight gain, secondary metabolic disturbances such as hyperglycemia, hyperprolactinemia, and cardiac conduction abnormalities. These side effects are health concerns for all patients but particularly for children and adolescents, who may require years of exposure to antipsychotics.

Weight gain. Younger patients may be particularly susceptible to weight gain with the use of the atypicals. In a state hospital adult population, Buckley et al found a strong inverse relationship between patient age and weight gain associated with atypical antipsychotic use.⁹ Key issues for pediatric populations are:

• Will children have difficulties losing weight over time?
  
• Will they stop their medications over time?
  
• Will they stop their medications because of this effect?
  
• Will they be further stigmatized at school because of obesity?
  
• Are they at increased risk to develop diabetes mellitus?
  
• What are the long-term consequences of antipsychotic-induced obesity and metabolic disturbances for this patient population?
  

 

Hyperprolactinemia in children and adolescents may lead to breast enlargement and galactorrhea, which are particularly distressing in this age group. Sustained elevation of prolactin may affect the regulation of other hormones, resulting in low estrogen and testosterone levels. The long-term impact of these changes on adolescent growth and development is unknown. Antipsychotic-induced hyperprolactinemia also may be associated with reduced bone density.¹⁰

Abnormal cardiac conduction. Thioridazine recently received a “black box” label warning from the FDA because of sudden deaths and a prolonged QTc interval seen on electrocardiogram (ECG) readings. Several other antipsychotics also show ECG evidence of QTc prolongation.¹¹ However, the clinical significance of this finding is unclear.

Box 2

Table

SUGGESTED DOSAGES OF ATYPICAL ANTIPSYCHOTICS

Drug	FDA-approved dosages for psychosis in adults	For psychosis in children and adolescents	For bipolar disorder in children and adolescents
Clozapine	Initial: 25 mg bid; increase gradually to 300 to 800 mg/d in divided doses	Not recommended for children under age 16 Initial: 12.5 to 25 mg bid; increase gradually to 300 to 450 mg/d (divided) Increased risk of seizures; potential for agranulocytosis	Limited research
Olanzapine	Psychosis. Initial: 5 to 10 mg qd or 5 mg bid; increase to 20 mg qd or 10 mg bid Bipolar disorder. Similar initial; lower maintenance (10 to 20 mg qd or 10 mg bid can often be obtained)	Clinical benefit in children age 10 at 2.5 to 10 mg/d; For age >10, 5 to 20 mg qd or 10 mg bid may be used Sedation and weight gain are common side effects	Clinically beneficial at dosages comparable to those used in psychosis Maintenance dosage may be lower than that required in a primary psychotic disorder
Quetiapine	Initial: 25 mg bid; increase to 300 to 800 mg/d divided in two to three doses	Initial: 12.5 mg bid (50 kg) Maintenance: 50 mg bid (50 kg) Few controlled trials in children	Limited research
Risperidone	Initial: 2 mg/d; may be increased to 4 to 6 mg/d in divided doses	Clinical trials indicate benefit at 0.25 to 0.5 mg qd or bid May be increased as needed to 0.5 to 1.5 mg/d in single or divided doses	Clinically beneficial at dosages comparable to those used in psychosis
Ziprasidone	Initial: 20 to 40 mg bid; may be increased to 40 to 80 mg bid	Preliminary studies suggest benefit at 10 to 20 mg bid, increasing to 20 to 60 mg bid Not recommended as first-line therapy in this population	Limited research
* The FDA has not approved a specific indication for these agents for use in children and adolescents. In adult patients, atypical antipsychotics have been approved for psychosis, and olanzapine is FDA-approved for psychosis and mood disorders.

 

Special care is required to decrease the risks associated with using antipsychotics in children and adolescents and to increase compliance with medication recommendations (Box 1).

Pharmacokinetics in children and adolescents

Administering medications to children and adolescents requires special precautions. Younger patients respond differently than adults to psychotropic medications because of differences in pharmacokinetics—how the body handles a drug—and pharmacodynamics—the drug’s effect on the body.

During a child’s growth and development, physiologic changes in absorption, distribution, metabolism, and excretion may affect drug delivery to target tissue (Box 2).^12,13 Maturation of brain regions and neurotransmitter systems also may alter a medication’s effect at different ages.

Antipsychotic dosage recommendations and therapeutic ranges for children and adolescents have been published but are extrapolated from adult studies because studies in children are lacking. There is danger, however, in using body weight and proportionately reducing an adult dosage to obtain a pediatric dosage. The plasma concentration may ultimately be subtherapeutic or toxic.¹⁴

The liver metabolizes most antipsychotics. The higher rate of hepatic metabolism in children would suggest that on a milligram-to-kilogram basis a child or adolescent would need a higher dose. Children, however, require smaller weight-adjusted doses of antipsychotics than do adults to achieve the same therapeutic effect.¹⁵ Children have a greater density of dopamine D-1 and D-2 receptors than do adults, suggesting a greater sensitivity to the beneficial and adverse effects of antipsychotics. To date, dopamine receptor occupancy in children/adolescents with schizophrenia has not been studied with positron emission tomography.

Summary. Compared with adults, children require a reduced milligram-to-kilogram dosage of antipsychotics to achieve the same therapeutic effect and avoid unwanted side effects. Children younger than age 10 or weighing less than 50 kg typically should start with the lowest starting dose, given once or twice a day (Table). The dose should be slowly increased based on the presence of side effects and remission of symptoms.

Maximum daily dosages for children weighing less than 50 kg should rarely exceed one-half of an adult antipsychotic dosage, particularly when used for symptoms of disorders other than primary psychosis. However, dosages closer to those used in adults may be necessary when treating primary psychosis in early-onset schizophrenia, especially in an adolescent (Box 3).

Box 3

Childhood/adolescent-onset schizophrenia

Typical antipsychotics appear to have limited efficacy in childhood/adolescent-onset schizophrenia, based on a small number of available case series and relatively short open-label trials.¹⁶ In a single-arm, placebo-controlled trial, haloperidol was effective in 16 children ages 5 to 12, but its use was associated with substantial EPS. A similar intolerance was demonstrated in a comparative trial of thioridazine and thiothixene.

Less is known about the incidence of tardive dyskinesia, but there is no reason to believe that the rate is lower in children and adolescents than in adults with schizophrenia (estimated at 5% per year for the first 5 years of treatment).

Clozapine. Information is emerging on the efficacy and tolerability of atypical antipsychotics in childhood/adolescent-onset schizophrenia.¹⁶ Clozapine has been studied more than other atypicals, in part because of the severity of early-onset schizophrenia and because clozapine has been used in clinical practice longer than the other agents in that class.

Early case reports and small open-labeled trials confirmed that clozapine was effective for children and adolescents with schizophrenia who had failed prior antipsychotic treatments.^17-19 A randomized, double-blind, controlled trial from the childhood schizophrenia division of the National Institute of Mental Health provided the most reliable information.¹⁷ In that 6-week treatment study, 21 severely ill adolescents (mean age 14) received clozapine, mean dosage 176 mg/d, or haloperidol, mean dosage 16 mg/d. Response to clozapine was greater for both positive and negative symptoms, and the difference was clinically and statistically significant. In addition, 62% of clozapine-treated patients were rated very much improved on the Clinical Global Impression (CGI) scale.

In the same trial, clozapine treatment was complicated by higher rates of adverse effects than are typically observed in adult studies:

 

• Sedation was reported in 90% of patients.
  
• 2 of 10 patients had a seizure during clozapine therapy.
  
• A 2% rate of agranulocytosis was disconcerting, given the lower adult rate (0.38%) and the brevity of the trial. As older age is a known risk factor for clozapine-induced agranulocytosis, it may be that children and the elderly are more susceptible to this side effect.
  

Risperidone. Most of the information on risperidone therapy in childhood/adolescent-onset schizophrenia is derived from small case series,⁷ which confirm its efficacy for both positive and negative symptoms. Recently, low-dose risperidone (less than 1.5 mg/d) was shown to be effective in young patients with schizophrenia’s prodrome.²⁰ In general, risperidone dosages of 1 to 2 mg/d are appropriate for patients with childhood/adolescent-onset schizophrenia. Children have been observed to be particularly sensitive to the drug’s EPS and prolactin-elevating effects.

Olanzapine has been effective in this patient population at dosages up to 10 mg/d.^7,16,21 In a pilot study, Kumra et al administered olanzapine to 23 children with schizophrenia who had not previously responded to neuroleptic treatment. After 8 weeks, the children improved on the Brief Psychiatric Rating Scale, the Scale for the Assessment for Negative Symptoms, and the Scale for the Assessment of Positive Symptoms.²¹

Similarities and differences in olanzapine’s side effects in adults and children/adolescents with schizophrenia were seen in a recent study. Children had more weight gain, sedation, and dystonia, whereas adults had significantly more cardiac arrhythmias.²²

Quetiapine. McConville and colleagues examined the efficacy and tolerability of quetiapine in 10 adolescents with chronic psychosis (7 with schizoaffective disorder and 3 with bipolar disorder). In this 3-week study, quetiapine was well-tolerated; in several patients, dosages exceeded 750 mg/d. Psychotic symptoms were reduced, and there was global improvement in functioning.²³

Other antipsychotics. There are no published data on the use of ziprasidone or aripiprazole in childhood/adolescent-onset schizophrenia.

Comparative data are very limited. One retrospective analysis compared the tolerability of risperidone, olanzapine, and quetiapine in 116 adolescent patients.²⁴ Over 3 months, 75 patients received risperidone (mean 2.6 mg/d), 16 received olanzapine (mean 13.3 mg/d), and 25 were treated with quetiapine (mean 210.3 mg/d). Weight gain was the most common side effect; patients gained an average 8.6 lb with risperidone, 7.2 lb with quetiapine, and 14.1 lb with olanzapine. EPS were treated in seven (10%) patients taking risperidone, four (25%) taking olanzapine, and no patients taking quetiapine.

Bipolar disorder

As in the adult population, there has been substantial use of antipsychotics in children and adolescents with bipolar illness. Bipolar I disorder affects an estimated 0.6% of adolescents and is even being diagnosed in prepubertal patients.

Lithium, valproate, carbamazapine, and adjunctive treatment with benzodiazapines traditionally have been used to treat bipolar I disorders. Although practice guidelines recommend lithium and divalproex sodium as first-line treatments for bipolar illness, these recommendations are generally based on a preference for first-line agents that have potential use in maintenance treatment. The benefit of medications in bipolar disorder, however, is two-fold:

• Initial pharmacotherapy is usually instituted to target manic or mixed symptoms, and continued treatment is necessary to avoid relapse. The new antipsychotics—particularly risperidone, olanzapine, and quetiapine—are beneficial to treat agitated mania and disrupted sleep that may impair function and/or mandate inpatient stabilization. The highly sedative properties offer an acute benefit in restoring disrupted sleep.
  
• Psychotic symptoms seen in mania may need to be targeted independent of the mood symptoms and would thus suggest the use of an antipsychotic. In early-onset bipolar disorder, antipsychotics are used primarily as adjuncts to mood stabilizers.
  

Evidence. The 1997 AACAP practice parameters on treating bipolar disorders included limited information on the use of antipsychotics. No studies had examined the efficacy of neuroleptics (i.e., haloperidol) in children and adolescents, and only one case study had been published on the benefit on a newer antipsychotic agent.²⁵ Since then, case reports and open studies have contributed to our understanding of the role the newer antipsychotics may play in treating this disorder:

• In the 1994 case report, an adolescent with bipolar disorder showed benefit when treated with clozapine.²⁶
  
• In a retrospective chart review, 28 children ages 4 to 17 with bipolar disorder (25 mixed and 3 hypomanic) were treated with adjunctive risperidone for 6 months. Most (82%) showed significant improvement in mania and aggression on a mean dosage of 1.7 +/- 1.3 mg/d. Attention-deficit/hyperactivity disorder symptoms improved in 8% of the patients.²⁷
  
• Affective symptoms (predominantly suggestive of bipolar disorder), aggression, and violent behavior in 11 children and adolescents ages 5 to 16 showed therapeutic response to an open trial of adjunctive low-dose (0.75 to 2.5 mg/d) risperidone.²⁸
  

 

Olanzapine. Recent interest in olanzapine’s thymoleptic propertities has contributed to its clinical use in bipolar disorder, specifically in psychotic mania. Olanzapine has also been studied as long-term maintenance therapy in bipolar disorder. In a 47-week study, adult patients receiving olanzapine improved significantly more than those receiving valproate (47% vs. 34% by the Young Mania Rating Scale) after 3 weeks. Both medications were effective throughout the long-term, randomized, double-blind study.²⁹

Two case series and one open trial have examined olanzapine as primary or adjunctive treatment for children and adolescents with bipolar disorder. In the open study, Frazier and colleagues gave olanzapine, 2.5 to 20 mg/d, to 23 children ages 5 to 14.³⁰ After 8 weeks, the response rate was 61% (defined as 30% or greater improvement on the Young Mania Rating Scale). Weight gain was the predominant side effect (mean increase 5 kg).

Chang and colleagues demonstrated “marked improvement” in CGI scores when using olanzapine as adjunctive therapy for three youths with bipolar disorder.³¹ Similar findings were reported when treating seven youths with acute mania.³² Olanzapine’s broad affinity for dopaminergic and serotonergic receptors may explain these positive outcomes.

Other atypicals. No studies have been published on the use of quetiapine, ziprasidone, or aripiprazole in childhood mood disorders.

Psychotic depression

Psychosis can complicate depression in adults and adolescents. In a small study of adolescents with psychotic depression, Gellar et al demonstrated conventional neuroleptics’ benefit in combination with antidepressants.³³ We have no data, however, on use of atypicals in childhood depression, and published accounts of depression in bipolar patients treated with atypicals are of some concern.

In one study,³⁴ four of six patients with bipolar disorder developed dysphoric mood within 3 months of starting risperidone. Two met the criteria for major depression and required antidepressant therapy. This finding was somewhat surprising, given risperidone’s antidepressant benefit in some adults, most likely due to its 5-HT2 antagonistic effect. Frazier and colleagues similiarly noted that one patient discontinued treatment during an open-label trial examining the benefit of olanzapine in juvenile bipolar disorder.³⁰

These findings in the adolescent bipolar population should not be ignored when you consider treating a primary depressive disorder with psychosis. Antipsychotics certainly can be useful for treating psychotic depression, especially acutely for stabilization and preventing harm to self. Atypical antipsychotics have consistently been proven to have less adverse side effects than typical antipsychotics and thus would be preferred in children and adolescents. Research is needed to examine possible worsening of dysphoria.

Related resources

• Hermann RC, Yang D, Ettner SL, et al. Prescription of antipsychotic drugs by office-based physicians in the United States, 1989-1997. Psychiatric Services 2002;53:425-30.
  
• Stigler KA, Potenza MN, McDougle CJ. Tolerability profile of atypical antipsychotics in children and adolescents (review). Paediatric Drugs 2001;3(12):927-94
  
• American Academy of Child and Adolescent Psychiatry http://www.aacap.org
  

Drug brand names

• Clozapine • Clozaril
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  
• Aripiprazole (investigational)
  

Disclosure

Dr. Londino reports that she serves as a consultant to Eli Lilly and Co.

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

Dr. Buckley reports that he receives grant support from and serves as a consultant and speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.