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Families and schools often pressure clinicians to “do something” when children or adolescents persistently bully, threaten, or injure others. This demand poses a treatment dilemma when psychosocial and educational interventions have failed to manage pediatric aggression.
Aggression is the main reason for drug therapy in youths with conduct disorder, but very little safety and efficacy data exist to help us choose medications. This places young patients at risk for polypharmacy, unmanaged symptoms, short-term side effects, and unknown long-term consequences of exposure to psychotropics.
Table 1
4 precautions when prescribing for pediatric aggression
|
| Source: American Academy of Child and Adolescent Psychiatry1 |
This article reviews the limited data on using medications to reduce aggression in children and adolescents, focusing on double-blind, placebo-controlled trials in conduct disorder. Based on this evidence and our clinical experience, we offer a sample case and treatment recommendations.
Prescribing principles
Precautions. When prescribing drugs to treat aggressive youth, remember the American Academy of Child and Adolescent Psychiatry’s precautions (Table 1)1 Recently published recommendations prepared by expert consensus are also valuable treatment guides.2
Linking treatment to diagnosis. Should we attempt to manage aggression as a manifestation of an underlying psychiatric disorder? Or should we treat it the same across all disorders? The latter approach is akin to the “fever model.”
Fever—regardless of cause—may be treated with a nonsteroidal anti-inflammatory drug. However, evidence from drug studies suggests that underlying psychiatric disorders should help determine the choice of aggression treatment. For example, a recent study in adults found that divalproex was effective for aggressive patients only within a specific diagnostic subgroup (in this case, cluster B personality disorders).3
Clinical experience also links aggression treatment with underlying diagnoses. For example, aggression secondary to agitated depression is treated with an antidepressant, whereas aggression secondary to command hallucinations in schizophrenia is treated with antipsychotics.
In treating aggression in conduct disorder (Table 2), first treat comorbid disorders—such as attention deficit/hyperactivity disorder (ADHD) or bipolar disorder—and address the child’s psychosocial and educational needs. Then if medication is appropriate, consider drugs with evidence of safety and efficacy, such as antipsychotics, lithium, and stimulants.
Antipsychotics
Three conventional antipsychotics—chlorpromazine, haloperidol, and thioridazine—are FDA-approved for controlling disruptive behaviors in children.4 No atypical antipsychotics are so indicated, but atypicals are preferred in children and adolescents because of lower risks for tardive dyskinesia, neuroleptic malignant syndrome, and extrapyramidal symptoms.2
Risperidone is the most-studied atypical antipsychotic for treating pediatric aggression, particularly in patients with low intellectual functioning or mental retardation. In a 6-week, double-blind, placebo-controlled trial, 118 children ages 5 to 12 with severely disruptive behavior and IQs of 36 to 84 were given low-dose risperidone (mean 1.16 mg/d). Risperidone reduced conduct problems significantly more than placebo, although aggression was not measured directly.5 Adverse events included somnolence, headache, vomiting, weight gain, and elevated serum prolactin. Similar results have been reported in other studies.6
Table 2
Diagnostic criteria for conduct disorder
| A. A repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated, as manifested by the persistence of three (or more) of the following criteria in the past 12 months, with at least one criterion present in the past 6 months: | |
| Aggression to people and animals | |
| 1. often bullies, threatens, or intimidates others | 5. has been physically cruel to animals |
| 2. often initiates physical fights | 6. has stolen while confronting a victim (such as mugging, purse snatching, extortion, armed robbery) |
| 3. has used a weapon that can cause serious physical harm to others (such as a bat, brick, broken bottle, knife, gun) | 7. has forced someone into sexual activity |
| 4. has been physically cruel to people | |
| Destruction of property | |
| 8. has deliberately engaged in fire setting with the intention of causing serious damage | 9. has deliberately destroyed others’ property (other than by fire setting) |
| Deceitfulness or theft | |
| 10. has broken into someone else’s house, building, or car | 12. has stolen items of nontrivial value without confronting a victim (such as shoplifting without breaking and entering, or forgery) |
| 11. often lies to obtain goods or favors or to avoid obligations(ie, “cons” others) | |
| Serious violation of rules | |
| 13. often stays out at night despite parental prohibitions, beginning before age 13 | 15. has run away from home overnight at least twice while living in parental or parental surrogate home (or once without returning for a lengthy period) |
| 14. is often truant from school, beginning before age 13 | |
| B. The disturbance in behavior causes clinically significant impairment in social, academic, or occupational functioning | |
| C. If the individual is age 18 or older, criteria are not met for antisocial personality disorder. | |
| Specify severity: | |
| Mild: few if any conduct problems in excess of those required to make the diagnosis and conduct problems cause only minor harm to others (such as lying, truancy, staying out after dark without permission) | |
| Moderate: number of conduct problems and effect on others intermediate between “mild” and severe” (such as stealing without confronting a victim, vandalism) | |
| Severe: many conduct problems in excess of those required to make the diagnosis or conduct problems cause considerable harm to others (such as forced sex, physical cruelty, use of a weapon, stealing while confronting a victim, breaking and entering) | |
| Source: Reprinted with permission from the Diagnostic and statistical manual of mental disorders, 4th ed., text revision. Copyright 2000. American Psychiatric Association. | |
JM, age 12, presented with his mother to address symptoms of hyperactivity and impulsive aggression. The boy also complained that his medications made him fall asleep during the day.
He is receiving five medications: a long-acting stimulant, atypical antipsychotic, anticonvulsant, alpha agonist, and selective serotonin reuptake inhibitor (SSRI). He had received numerous other medications, but prescription records are unavailable or incomplete.
Diagnostic history. Since age 5, JM has been diagnosed as having attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, bipolar disorder, major depressive disorder, and learning disorders. On examination, the boy met DSM-IV criteria for ADHD, learning disorders, and conduct disorder (Table 2). He has a history of starting fights with peers, bullying, destroying property, lying, and stealing from stores and peers.
His mother stated that her son had always had irritable and labile periods, especially when he did not get his way. She was told during a previous psychiatric evaluation that the boy’s "mood swings" indicated bipolar disorder. On examination, however, he had no other bipolar symptoms, and his condition was chronic, not cyclic.
JM typically cries when he does not get his way, his mother reported, but he has no history of sleep or appetite changes that could suggest depression. He is happy when he can do as he pleases.
Reducing medications. After reviewing JM’s medications and performing the psychiatric assessment, the psychiatrist developed a plan to maximize his psychosocial and educational treatments and alter his medications and dosages. The first step was to increase the stimulant dosage to determine whether JM would be less hyperactive and impulsively aggressive.
The psychiatrist was concerned that the anticonvulsant, alpha agonist, and SSRI were not helping and could cause adverse events. He discussed slowly weaning these drugs one at a time with JM and his mother, and they agreed. The goal was to manage JM over time and to reduce his medications to one (ideally) or two (if necessary), possibly continuing the atypical antipsychotic.
Risperidone also reduced aggression in children with normal intelligence in one small study.7 As a cautionary note, however, long-term risperidone treatment has been associated with withdrawal dyskinesias.8
Olanzapine, quetiapine, ziprasidone, and aripiprazole are less well-studied for treating pediatric aggression but are preferable to conventional agents when antipsychotics are considered.
Recommendation. Expert consensus opinion2 recommends using atypicals when psychosocial treatments and first-line medications for primary conditions have failed. Start with low dosages, and titrate up slowly while monitoring symptoms and side effects. Because no studies have compared any atypical’s efficacy over others for aggressive behavior, base your choices on:
- discussions with the patient and family (Box 1)
- medical comorbidities
- how the patient responded to antipsychotics in the past
- side-effect profile
- long-term treatment planning.2
If the patient cannot tolerate the medication or does not respond after 4 to 6 weeks, try switching atypicals. To improve partial response, consider adding a mood stabilizer such as lithium or divalproex. If aggressive symptoms remit for 6 months or longer, attempt to taper or discontinue the antipsychotic.2
Lithium
In placebo-controlled trials, lithium reduced aggression in:
- male prisoners ages 16 to 24.9
- children ages 7 and 12 with conduct disorder10
- children and adolescents ages 10 to 17 with conduct disorder.11
Among these studies, only ours11 specifically measured aggression. We randomly assigned 40 children to receive 4 weeks of lithium, 900 to 2,100 mg/d (mean 1,425 ± 321 mg/d), or placebo. Serum lithium levels were 0.78 to 1.55 mEq/L (mean 1.07 ± 0.19 mEq/L). We used the Overt Aggression Scale (OAS)12,13 (see Related resources) to track frequency and severity of verbal aggression, aggression against objects, aggression against others, and self-aggression.
Lithium reduced aggression more than did placebo, as measured by the clinician-rated Clinical Global Impressions (CGI) scale and staff-rated Global Clinical Judgments (Consensus) Scale (GCJCS). The CGI showed a 70% response rate with lithium and 20% with placebo. Similarly, the GCJCS scale showed 80% response with lithium and 30% with placebo.
The aggression reduction with lithium was statistically significant and clinically evident. Most subjects (37 of 40) experienced at least one adverse event, however, whether receiving lithium or placebo. Nausea, vomiting, and urinary frequency were significantly more common in the lithium-treated group than with placebo. Fewer adverse events were reported in a similar outpatient study,14 probably because of less-frequent monitoring.
Lithium did not reduce aggression in adolescent girls treated for 2 weeks15 or in an outpatient study of children with ADHD.16
Recommendation. Lithium has shown efficacy for reducing severe aggression in hospitalized children with conduct disorder but not in similar outpatients. Consider this drug to reduce severe aggression in children with conduct disorder, especially if they have failed other treatments.
Anticonvulsants
Anticonvulsants have been used to decrease aggression for more than 50 years, and epidemiologic data show their use is increasing markedly.17 Few controlled studies support this prescribing trend, however.18
Initial reports suggested that anticonvulsants reduce disruptive behaviors, but more-critically designed studies have not supported this finding. For example, phenytoin sodium (diphenylhydantoin) demonstrated efficacy in open trials, but controlled trials found this anticonvulsant no more effective than placebo. In fact, placebo may have reduced aggression more than the active drug. Likewise, earlier controlled trials of carbamazepine indicated efficacy, but more-carefully designed trials using specific measures of aggression did not.
Divalproex is the anticonvulsant most commonly used for aggression in children and adolescents. Only one small, placebo-controlled study has found it effective in reducing aggression in children.19
Twenty children ages 10 to 18 with conduct disorder or oppositional defiant disorder were randomized to divalproex, 750 to 1,500 mg/d, or placebo. Eighteen completed the first phase, and 15 crossed over to the other treatment. Concomitant drug treatment, including stimulants, was allowed. The authors reported that 12 of 15 subjects showed some response to divalproex.
A 7-week study compared divalproex in high dosages (up to 1,500 mg/d) versus low dosages (up to 250 mg/d). This study was not placebo-controlled, but aggression was reduced more in the high-dosage than in the low-dosage group.20
Recommendation. If you use an anticonvulsant, first obtain informed consent from the patient and parent. Divalproex causes weight gain and has been associated with increased risk of polycystic ovary syndrome with masculinizing effects.21
Double-blind, placebo-controlled studies of divalproex and other anticonvulsants in treating aggression are needed, particularly as prescriptions for these agents are rising.
Stimulants
Some small controlled studies suggest that stimulants can reduce aggression in children with ADHD, but their effects on aggression in conduct disorder have not been well studied. Aggression was not measured directly in the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD.21 Most other studies have been small and included children with ADHD but not necessarily conduct disorder.
Recommendation. Stimulants may help reduce aggression in children with ADHD, but studies gauging their effects in conduct disorder are needed.
Alpha agonists
Alpha agonists such as clonidine and guanfacine are increasingly being used to treat children with disruptive disorders, despite limited evidence. The small controlled studies that examined alpha agonists as monotherapy or add-ons in this population did not directly measure aggression.22,23
Recommendation. Little data support alpha agonists for reducing aggression. They should probably be considered second-line treatment.
SSRIs
No double-blind, placebo-controlled studies have tested any selective serotonin reuptake inhibitor (SSRIs) for reducing aggression in conduct disorder. In a 6-week open study, citalopram (mean 27 mg/d) reduced impulsive aggression in 12 children with mixed diagnoses, as measured by the modified OAS,13 Child Behavior Checklist, and CGI.24
Recommendation. Use caution when prescribing SSRIs to aggressive youth, as these drugs may contribute to aggression in some mood-disordered children. More evidence of SSRIs’ safety and efficacy in this population is needed.
- Overt Aggression Scale. In: Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsiveaggressive behavior. J Neuropsychiatry 1991;3(2):S44-S51.
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Citalopram • Celexa
- Chlorpromazine • Thorazine
- Clonidine • Catapres
- Phenytoin sodium • Dilantin
- Divalproex • Depakote
- Guanfacine • Tenex
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Disclosure
Dr. Malone receives research support from Pfizer Inc. and Eli Lilly and Co. and is a consultant to Janssen Pharmaceutica.
Dr. Delaney is a consultant to Shire Pharmaceuticals.
Dr. Sheikh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Prescribing psychoactive medications for children and adolescents American Academy of Child and Adolescent Psychiatry policy statement, adopted Sept. 20, 2001. Available at:http://www.aacap.org/publications/policy/ps41.htm Accessed Jan. 15, 2004.
2. Pappadopulos E, MacIntyre JC, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145-61.
3. Hollander E, Tracy KA, Swann AC, et al. Divalproex in the treatment of impulsive aggression: efficacy in Cluster B personality disorders. Neuropsychopharmacology 2003;28:1186-97.
4. Physician’s Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.
5. Aman MG, DeSmedt G, Derivan A, et al. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry 2002;159:1337-46.
6. Snyder R, Turgay A, Aman M, et al. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
7. Findling RL, McNamara NK, Branicky LA, et al. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry 2000;39:509-16.
8. Malone RP, Maislin G, Choudhury MS, et al. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry 2002;41(2):140-7.
9. Sheard MH, Marini JL, Bridges CI, Wagner E. The effect of lithium on impulsive aggressive behavior in man. Am J Psychiatry 1976;133(12):1409-13.
10. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34:445-53.
11. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000a;57(7):649-54.
12. Yudofsky SC, Silver JM, Jackson W, et al. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143:35-9.
13. Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsive aggressive behavior. J Neuropsychiatry 1991;3:S44-S5.
14. Malone RP, Delaney MA, Gifford C. Adverse events during lithium treatment in children varies by setting. Miami Beach, FL: American Academy of Child and Adolescent Psychiatry annual meeting, 2003.
15. Rifkin A, Karajgi B, Dicker R, et al. Lithium treatment of conduct disorders in adolescents. Am J Psychiatry 1997;154:554-5.
16. Klein RG. Preliminary results: lithium effects in conduct disorders. New Orleans: American Psychiatric Association annual meeting, 1991.
17. Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17-25.
18. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment. New York: Marcel Dekker, 2003b;331-49.
19. Donovan SJ, Stewart JW, Nunes EV, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000;157:818-20.
20. Steiner H. A randomized clinical trial of divalproex sodium in conduct disorders. J Clin Psychiatry (in press).
21. Isojarvi JT, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:579-84.
22. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073-86.
23. Conner DF, Barkley RA, Davis HT. A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 2000;39:15-25.
24. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;886-94.
25. Armenteros JL, Lewis JE. Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study. J Am Acad Child Adolesc Psychiatry 2002;41:522-9.
Families and schools often pressure clinicians to “do something” when children or adolescents persistently bully, threaten, or injure others. This demand poses a treatment dilemma when psychosocial and educational interventions have failed to manage pediatric aggression.
Aggression is the main reason for drug therapy in youths with conduct disorder, but very little safety and efficacy data exist to help us choose medications. This places young patients at risk for polypharmacy, unmanaged symptoms, short-term side effects, and unknown long-term consequences of exposure to psychotropics.
Table 1
4 precautions when prescribing for pediatric aggression
|
| Source: American Academy of Child and Adolescent Psychiatry1 |
This article reviews the limited data on using medications to reduce aggression in children and adolescents, focusing on double-blind, placebo-controlled trials in conduct disorder. Based on this evidence and our clinical experience, we offer a sample case and treatment recommendations.
Prescribing principles
Precautions. When prescribing drugs to treat aggressive youth, remember the American Academy of Child and Adolescent Psychiatry’s precautions (Table 1)1 Recently published recommendations prepared by expert consensus are also valuable treatment guides.2
Linking treatment to diagnosis. Should we attempt to manage aggression as a manifestation of an underlying psychiatric disorder? Or should we treat it the same across all disorders? The latter approach is akin to the “fever model.”
Fever—regardless of cause—may be treated with a nonsteroidal anti-inflammatory drug. However, evidence from drug studies suggests that underlying psychiatric disorders should help determine the choice of aggression treatment. For example, a recent study in adults found that divalproex was effective for aggressive patients only within a specific diagnostic subgroup (in this case, cluster B personality disorders).3
Clinical experience also links aggression treatment with underlying diagnoses. For example, aggression secondary to agitated depression is treated with an antidepressant, whereas aggression secondary to command hallucinations in schizophrenia is treated with antipsychotics.
In treating aggression in conduct disorder (Table 2), first treat comorbid disorders—such as attention deficit/hyperactivity disorder (ADHD) or bipolar disorder—and address the child’s psychosocial and educational needs. Then if medication is appropriate, consider drugs with evidence of safety and efficacy, such as antipsychotics, lithium, and stimulants.
Antipsychotics
Three conventional antipsychotics—chlorpromazine, haloperidol, and thioridazine—are FDA-approved for controlling disruptive behaviors in children.4 No atypical antipsychotics are so indicated, but atypicals are preferred in children and adolescents because of lower risks for tardive dyskinesia, neuroleptic malignant syndrome, and extrapyramidal symptoms.2
Risperidone is the most-studied atypical antipsychotic for treating pediatric aggression, particularly in patients with low intellectual functioning or mental retardation. In a 6-week, double-blind, placebo-controlled trial, 118 children ages 5 to 12 with severely disruptive behavior and IQs of 36 to 84 were given low-dose risperidone (mean 1.16 mg/d). Risperidone reduced conduct problems significantly more than placebo, although aggression was not measured directly.5 Adverse events included somnolence, headache, vomiting, weight gain, and elevated serum prolactin. Similar results have been reported in other studies.6
Table 2
Diagnostic criteria for conduct disorder
| A. A repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated, as manifested by the persistence of three (or more) of the following criteria in the past 12 months, with at least one criterion present in the past 6 months: | |
| Aggression to people and animals | |
| 1. often bullies, threatens, or intimidates others | 5. has been physically cruel to animals |
| 2. often initiates physical fights | 6. has stolen while confronting a victim (such as mugging, purse snatching, extortion, armed robbery) |
| 3. has used a weapon that can cause serious physical harm to others (such as a bat, brick, broken bottle, knife, gun) | 7. has forced someone into sexual activity |
| 4. has been physically cruel to people | |
| Destruction of property | |
| 8. has deliberately engaged in fire setting with the intention of causing serious damage | 9. has deliberately destroyed others’ property (other than by fire setting) |
| Deceitfulness or theft | |
| 10. has broken into someone else’s house, building, or car | 12. has stolen items of nontrivial value without confronting a victim (such as shoplifting without breaking and entering, or forgery) |
| 11. often lies to obtain goods or favors or to avoid obligations(ie, “cons” others) | |
| Serious violation of rules | |
| 13. often stays out at night despite parental prohibitions, beginning before age 13 | 15. has run away from home overnight at least twice while living in parental or parental surrogate home (or once without returning for a lengthy period) |
| 14. is often truant from school, beginning before age 13 | |
| B. The disturbance in behavior causes clinically significant impairment in social, academic, or occupational functioning | |
| C. If the individual is age 18 or older, criteria are not met for antisocial personality disorder. | |
| Specify severity: | |
| Mild: few if any conduct problems in excess of those required to make the diagnosis and conduct problems cause only minor harm to others (such as lying, truancy, staying out after dark without permission) | |
| Moderate: number of conduct problems and effect on others intermediate between “mild” and severe” (such as stealing without confronting a victim, vandalism) | |
| Severe: many conduct problems in excess of those required to make the diagnosis or conduct problems cause considerable harm to others (such as forced sex, physical cruelty, use of a weapon, stealing while confronting a victim, breaking and entering) | |
| Source: Reprinted with permission from the Diagnostic and statistical manual of mental disorders, 4th ed., text revision. Copyright 2000. American Psychiatric Association. | |
JM, age 12, presented with his mother to address symptoms of hyperactivity and impulsive aggression. The boy also complained that his medications made him fall asleep during the day.
He is receiving five medications: a long-acting stimulant, atypical antipsychotic, anticonvulsant, alpha agonist, and selective serotonin reuptake inhibitor (SSRI). He had received numerous other medications, but prescription records are unavailable or incomplete.
Diagnostic history. Since age 5, JM has been diagnosed as having attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, bipolar disorder, major depressive disorder, and learning disorders. On examination, the boy met DSM-IV criteria for ADHD, learning disorders, and conduct disorder (Table 2). He has a history of starting fights with peers, bullying, destroying property, lying, and stealing from stores and peers.
His mother stated that her son had always had irritable and labile periods, especially when he did not get his way. She was told during a previous psychiatric evaluation that the boy’s "mood swings" indicated bipolar disorder. On examination, however, he had no other bipolar symptoms, and his condition was chronic, not cyclic.
JM typically cries when he does not get his way, his mother reported, but he has no history of sleep or appetite changes that could suggest depression. He is happy when he can do as he pleases.
Reducing medications. After reviewing JM’s medications and performing the psychiatric assessment, the psychiatrist developed a plan to maximize his psychosocial and educational treatments and alter his medications and dosages. The first step was to increase the stimulant dosage to determine whether JM would be less hyperactive and impulsively aggressive.
The psychiatrist was concerned that the anticonvulsant, alpha agonist, and SSRI were not helping and could cause adverse events. He discussed slowly weaning these drugs one at a time with JM and his mother, and they agreed. The goal was to manage JM over time and to reduce his medications to one (ideally) or two (if necessary), possibly continuing the atypical antipsychotic.
Risperidone also reduced aggression in children with normal intelligence in one small study.7 As a cautionary note, however, long-term risperidone treatment has been associated with withdrawal dyskinesias.8
Olanzapine, quetiapine, ziprasidone, and aripiprazole are less well-studied for treating pediatric aggression but are preferable to conventional agents when antipsychotics are considered.
Recommendation. Expert consensus opinion2 recommends using atypicals when psychosocial treatments and first-line medications for primary conditions have failed. Start with low dosages, and titrate up slowly while monitoring symptoms and side effects. Because no studies have compared any atypical’s efficacy over others for aggressive behavior, base your choices on:
- discussions with the patient and family (Box 1)
- medical comorbidities
- how the patient responded to antipsychotics in the past
- side-effect profile
- long-term treatment planning.2
If the patient cannot tolerate the medication or does not respond after 4 to 6 weeks, try switching atypicals. To improve partial response, consider adding a mood stabilizer such as lithium or divalproex. If aggressive symptoms remit for 6 months or longer, attempt to taper or discontinue the antipsychotic.2
Lithium
In placebo-controlled trials, lithium reduced aggression in:
- male prisoners ages 16 to 24.9
- children ages 7 and 12 with conduct disorder10
- children and adolescents ages 10 to 17 with conduct disorder.11
Among these studies, only ours11 specifically measured aggression. We randomly assigned 40 children to receive 4 weeks of lithium, 900 to 2,100 mg/d (mean 1,425 ± 321 mg/d), or placebo. Serum lithium levels were 0.78 to 1.55 mEq/L (mean 1.07 ± 0.19 mEq/L). We used the Overt Aggression Scale (OAS)12,13 (see Related resources) to track frequency and severity of verbal aggression, aggression against objects, aggression against others, and self-aggression.
Lithium reduced aggression more than did placebo, as measured by the clinician-rated Clinical Global Impressions (CGI) scale and staff-rated Global Clinical Judgments (Consensus) Scale (GCJCS). The CGI showed a 70% response rate with lithium and 20% with placebo. Similarly, the GCJCS scale showed 80% response with lithium and 30% with placebo.
The aggression reduction with lithium was statistically significant and clinically evident. Most subjects (37 of 40) experienced at least one adverse event, however, whether receiving lithium or placebo. Nausea, vomiting, and urinary frequency were significantly more common in the lithium-treated group than with placebo. Fewer adverse events were reported in a similar outpatient study,14 probably because of less-frequent monitoring.
Lithium did not reduce aggression in adolescent girls treated for 2 weeks15 or in an outpatient study of children with ADHD.16
Recommendation. Lithium has shown efficacy for reducing severe aggression in hospitalized children with conduct disorder but not in similar outpatients. Consider this drug to reduce severe aggression in children with conduct disorder, especially if they have failed other treatments.
Anticonvulsants
Anticonvulsants have been used to decrease aggression for more than 50 years, and epidemiologic data show their use is increasing markedly.17 Few controlled studies support this prescribing trend, however.18
Initial reports suggested that anticonvulsants reduce disruptive behaviors, but more-critically designed studies have not supported this finding. For example, phenytoin sodium (diphenylhydantoin) demonstrated efficacy in open trials, but controlled trials found this anticonvulsant no more effective than placebo. In fact, placebo may have reduced aggression more than the active drug. Likewise, earlier controlled trials of carbamazepine indicated efficacy, but more-carefully designed trials using specific measures of aggression did not.
Divalproex is the anticonvulsant most commonly used for aggression in children and adolescents. Only one small, placebo-controlled study has found it effective in reducing aggression in children.19
Twenty children ages 10 to 18 with conduct disorder or oppositional defiant disorder were randomized to divalproex, 750 to 1,500 mg/d, or placebo. Eighteen completed the first phase, and 15 crossed over to the other treatment. Concomitant drug treatment, including stimulants, was allowed. The authors reported that 12 of 15 subjects showed some response to divalproex.
A 7-week study compared divalproex in high dosages (up to 1,500 mg/d) versus low dosages (up to 250 mg/d). This study was not placebo-controlled, but aggression was reduced more in the high-dosage than in the low-dosage group.20
Recommendation. If you use an anticonvulsant, first obtain informed consent from the patient and parent. Divalproex causes weight gain and has been associated with increased risk of polycystic ovary syndrome with masculinizing effects.21
Double-blind, placebo-controlled studies of divalproex and other anticonvulsants in treating aggression are needed, particularly as prescriptions for these agents are rising.
Stimulants
Some small controlled studies suggest that stimulants can reduce aggression in children with ADHD, but their effects on aggression in conduct disorder have not been well studied. Aggression was not measured directly in the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD.21 Most other studies have been small and included children with ADHD but not necessarily conduct disorder.
Recommendation. Stimulants may help reduce aggression in children with ADHD, but studies gauging their effects in conduct disorder are needed.
Alpha agonists
Alpha agonists such as clonidine and guanfacine are increasingly being used to treat children with disruptive disorders, despite limited evidence. The small controlled studies that examined alpha agonists as monotherapy or add-ons in this population did not directly measure aggression.22,23
Recommendation. Little data support alpha agonists for reducing aggression. They should probably be considered second-line treatment.
SSRIs
No double-blind, placebo-controlled studies have tested any selective serotonin reuptake inhibitor (SSRIs) for reducing aggression in conduct disorder. In a 6-week open study, citalopram (mean 27 mg/d) reduced impulsive aggression in 12 children with mixed diagnoses, as measured by the modified OAS,13 Child Behavior Checklist, and CGI.24
Recommendation. Use caution when prescribing SSRIs to aggressive youth, as these drugs may contribute to aggression in some mood-disordered children. More evidence of SSRIs’ safety and efficacy in this population is needed.
- Overt Aggression Scale. In: Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsiveaggressive behavior. J Neuropsychiatry 1991;3(2):S44-S51.
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Citalopram • Celexa
- Chlorpromazine • Thorazine
- Clonidine • Catapres
- Phenytoin sodium • Dilantin
- Divalproex • Depakote
- Guanfacine • Tenex
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Disclosure
Dr. Malone receives research support from Pfizer Inc. and Eli Lilly and Co. and is a consultant to Janssen Pharmaceutica.
Dr. Delaney is a consultant to Shire Pharmaceuticals.
Dr. Sheikh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Families and schools often pressure clinicians to “do something” when children or adolescents persistently bully, threaten, or injure others. This demand poses a treatment dilemma when psychosocial and educational interventions have failed to manage pediatric aggression.
Aggression is the main reason for drug therapy in youths with conduct disorder, but very little safety and efficacy data exist to help us choose medications. This places young patients at risk for polypharmacy, unmanaged symptoms, short-term side effects, and unknown long-term consequences of exposure to psychotropics.
Table 1
4 precautions when prescribing for pediatric aggression
|
| Source: American Academy of Child and Adolescent Psychiatry1 |
This article reviews the limited data on using medications to reduce aggression in children and adolescents, focusing on double-blind, placebo-controlled trials in conduct disorder. Based on this evidence and our clinical experience, we offer a sample case and treatment recommendations.
Prescribing principles
Precautions. When prescribing drugs to treat aggressive youth, remember the American Academy of Child and Adolescent Psychiatry’s precautions (Table 1)1 Recently published recommendations prepared by expert consensus are also valuable treatment guides.2
Linking treatment to diagnosis. Should we attempt to manage aggression as a manifestation of an underlying psychiatric disorder? Or should we treat it the same across all disorders? The latter approach is akin to the “fever model.”
Fever—regardless of cause—may be treated with a nonsteroidal anti-inflammatory drug. However, evidence from drug studies suggests that underlying psychiatric disorders should help determine the choice of aggression treatment. For example, a recent study in adults found that divalproex was effective for aggressive patients only within a specific diagnostic subgroup (in this case, cluster B personality disorders).3
Clinical experience also links aggression treatment with underlying diagnoses. For example, aggression secondary to agitated depression is treated with an antidepressant, whereas aggression secondary to command hallucinations in schizophrenia is treated with antipsychotics.
In treating aggression in conduct disorder (Table 2), first treat comorbid disorders—such as attention deficit/hyperactivity disorder (ADHD) or bipolar disorder—and address the child’s psychosocial and educational needs. Then if medication is appropriate, consider drugs with evidence of safety and efficacy, such as antipsychotics, lithium, and stimulants.
Antipsychotics
Three conventional antipsychotics—chlorpromazine, haloperidol, and thioridazine—are FDA-approved for controlling disruptive behaviors in children.4 No atypical antipsychotics are so indicated, but atypicals are preferred in children and adolescents because of lower risks for tardive dyskinesia, neuroleptic malignant syndrome, and extrapyramidal symptoms.2
Risperidone is the most-studied atypical antipsychotic for treating pediatric aggression, particularly in patients with low intellectual functioning or mental retardation. In a 6-week, double-blind, placebo-controlled trial, 118 children ages 5 to 12 with severely disruptive behavior and IQs of 36 to 84 were given low-dose risperidone (mean 1.16 mg/d). Risperidone reduced conduct problems significantly more than placebo, although aggression was not measured directly.5 Adverse events included somnolence, headache, vomiting, weight gain, and elevated serum prolactin. Similar results have been reported in other studies.6
Table 2
Diagnostic criteria for conduct disorder
| A. A repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated, as manifested by the persistence of three (or more) of the following criteria in the past 12 months, with at least one criterion present in the past 6 months: | |
| Aggression to people and animals | |
| 1. often bullies, threatens, or intimidates others | 5. has been physically cruel to animals |
| 2. often initiates physical fights | 6. has stolen while confronting a victim (such as mugging, purse snatching, extortion, armed robbery) |
| 3. has used a weapon that can cause serious physical harm to others (such as a bat, brick, broken bottle, knife, gun) | 7. has forced someone into sexual activity |
| 4. has been physically cruel to people | |
| Destruction of property | |
| 8. has deliberately engaged in fire setting with the intention of causing serious damage | 9. has deliberately destroyed others’ property (other than by fire setting) |
| Deceitfulness or theft | |
| 10. has broken into someone else’s house, building, or car | 12. has stolen items of nontrivial value without confronting a victim (such as shoplifting without breaking and entering, or forgery) |
| 11. often lies to obtain goods or favors or to avoid obligations(ie, “cons” others) | |
| Serious violation of rules | |
| 13. often stays out at night despite parental prohibitions, beginning before age 13 | 15. has run away from home overnight at least twice while living in parental or parental surrogate home (or once without returning for a lengthy period) |
| 14. is often truant from school, beginning before age 13 | |
| B. The disturbance in behavior causes clinically significant impairment in social, academic, or occupational functioning | |
| C. If the individual is age 18 or older, criteria are not met for antisocial personality disorder. | |
| Specify severity: | |
| Mild: few if any conduct problems in excess of those required to make the diagnosis and conduct problems cause only minor harm to others (such as lying, truancy, staying out after dark without permission) | |
| Moderate: number of conduct problems and effect on others intermediate between “mild” and severe” (such as stealing without confronting a victim, vandalism) | |
| Severe: many conduct problems in excess of those required to make the diagnosis or conduct problems cause considerable harm to others (such as forced sex, physical cruelty, use of a weapon, stealing while confronting a victim, breaking and entering) | |
| Source: Reprinted with permission from the Diagnostic and statistical manual of mental disorders, 4th ed., text revision. Copyright 2000. American Psychiatric Association. | |
JM, age 12, presented with his mother to address symptoms of hyperactivity and impulsive aggression. The boy also complained that his medications made him fall asleep during the day.
He is receiving five medications: a long-acting stimulant, atypical antipsychotic, anticonvulsant, alpha agonist, and selective serotonin reuptake inhibitor (SSRI). He had received numerous other medications, but prescription records are unavailable or incomplete.
Diagnostic history. Since age 5, JM has been diagnosed as having attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, bipolar disorder, major depressive disorder, and learning disorders. On examination, the boy met DSM-IV criteria for ADHD, learning disorders, and conduct disorder (Table 2). He has a history of starting fights with peers, bullying, destroying property, lying, and stealing from stores and peers.
His mother stated that her son had always had irritable and labile periods, especially when he did not get his way. She was told during a previous psychiatric evaluation that the boy’s "mood swings" indicated bipolar disorder. On examination, however, he had no other bipolar symptoms, and his condition was chronic, not cyclic.
JM typically cries when he does not get his way, his mother reported, but he has no history of sleep or appetite changes that could suggest depression. He is happy when he can do as he pleases.
Reducing medications. After reviewing JM’s medications and performing the psychiatric assessment, the psychiatrist developed a plan to maximize his psychosocial and educational treatments and alter his medications and dosages. The first step was to increase the stimulant dosage to determine whether JM would be less hyperactive and impulsively aggressive.
The psychiatrist was concerned that the anticonvulsant, alpha agonist, and SSRI were not helping and could cause adverse events. He discussed slowly weaning these drugs one at a time with JM and his mother, and they agreed. The goal was to manage JM over time and to reduce his medications to one (ideally) or two (if necessary), possibly continuing the atypical antipsychotic.
Risperidone also reduced aggression in children with normal intelligence in one small study.7 As a cautionary note, however, long-term risperidone treatment has been associated with withdrawal dyskinesias.8
Olanzapine, quetiapine, ziprasidone, and aripiprazole are less well-studied for treating pediatric aggression but are preferable to conventional agents when antipsychotics are considered.
Recommendation. Expert consensus opinion2 recommends using atypicals when psychosocial treatments and first-line medications for primary conditions have failed. Start with low dosages, and titrate up slowly while monitoring symptoms and side effects. Because no studies have compared any atypical’s efficacy over others for aggressive behavior, base your choices on:
- discussions with the patient and family (Box 1)
- medical comorbidities
- how the patient responded to antipsychotics in the past
- side-effect profile
- long-term treatment planning.2
If the patient cannot tolerate the medication or does not respond after 4 to 6 weeks, try switching atypicals. To improve partial response, consider adding a mood stabilizer such as lithium or divalproex. If aggressive symptoms remit for 6 months or longer, attempt to taper or discontinue the antipsychotic.2
Lithium
In placebo-controlled trials, lithium reduced aggression in:
- male prisoners ages 16 to 24.9
- children ages 7 and 12 with conduct disorder10
- children and adolescents ages 10 to 17 with conduct disorder.11
Among these studies, only ours11 specifically measured aggression. We randomly assigned 40 children to receive 4 weeks of lithium, 900 to 2,100 mg/d (mean 1,425 ± 321 mg/d), or placebo. Serum lithium levels were 0.78 to 1.55 mEq/L (mean 1.07 ± 0.19 mEq/L). We used the Overt Aggression Scale (OAS)12,13 (see Related resources) to track frequency and severity of verbal aggression, aggression against objects, aggression against others, and self-aggression.
Lithium reduced aggression more than did placebo, as measured by the clinician-rated Clinical Global Impressions (CGI) scale and staff-rated Global Clinical Judgments (Consensus) Scale (GCJCS). The CGI showed a 70% response rate with lithium and 20% with placebo. Similarly, the GCJCS scale showed 80% response with lithium and 30% with placebo.
The aggression reduction with lithium was statistically significant and clinically evident. Most subjects (37 of 40) experienced at least one adverse event, however, whether receiving lithium or placebo. Nausea, vomiting, and urinary frequency were significantly more common in the lithium-treated group than with placebo. Fewer adverse events were reported in a similar outpatient study,14 probably because of less-frequent monitoring.
Lithium did not reduce aggression in adolescent girls treated for 2 weeks15 or in an outpatient study of children with ADHD.16
Recommendation. Lithium has shown efficacy for reducing severe aggression in hospitalized children with conduct disorder but not in similar outpatients. Consider this drug to reduce severe aggression in children with conduct disorder, especially if they have failed other treatments.
Anticonvulsants
Anticonvulsants have been used to decrease aggression for more than 50 years, and epidemiologic data show their use is increasing markedly.17 Few controlled studies support this prescribing trend, however.18
Initial reports suggested that anticonvulsants reduce disruptive behaviors, but more-critically designed studies have not supported this finding. For example, phenytoin sodium (diphenylhydantoin) demonstrated efficacy in open trials, but controlled trials found this anticonvulsant no more effective than placebo. In fact, placebo may have reduced aggression more than the active drug. Likewise, earlier controlled trials of carbamazepine indicated efficacy, but more-carefully designed trials using specific measures of aggression did not.
Divalproex is the anticonvulsant most commonly used for aggression in children and adolescents. Only one small, placebo-controlled study has found it effective in reducing aggression in children.19
Twenty children ages 10 to 18 with conduct disorder or oppositional defiant disorder were randomized to divalproex, 750 to 1,500 mg/d, or placebo. Eighteen completed the first phase, and 15 crossed over to the other treatment. Concomitant drug treatment, including stimulants, was allowed. The authors reported that 12 of 15 subjects showed some response to divalproex.
A 7-week study compared divalproex in high dosages (up to 1,500 mg/d) versus low dosages (up to 250 mg/d). This study was not placebo-controlled, but aggression was reduced more in the high-dosage than in the low-dosage group.20
Recommendation. If you use an anticonvulsant, first obtain informed consent from the patient and parent. Divalproex causes weight gain and has been associated with increased risk of polycystic ovary syndrome with masculinizing effects.21
Double-blind, placebo-controlled studies of divalproex and other anticonvulsants in treating aggression are needed, particularly as prescriptions for these agents are rising.
Stimulants
Some small controlled studies suggest that stimulants can reduce aggression in children with ADHD, but their effects on aggression in conduct disorder have not been well studied. Aggression was not measured directly in the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD.21 Most other studies have been small and included children with ADHD but not necessarily conduct disorder.
Recommendation. Stimulants may help reduce aggression in children with ADHD, but studies gauging their effects in conduct disorder are needed.
Alpha agonists
Alpha agonists such as clonidine and guanfacine are increasingly being used to treat children with disruptive disorders, despite limited evidence. The small controlled studies that examined alpha agonists as monotherapy or add-ons in this population did not directly measure aggression.22,23
Recommendation. Little data support alpha agonists for reducing aggression. They should probably be considered second-line treatment.
SSRIs
No double-blind, placebo-controlled studies have tested any selective serotonin reuptake inhibitor (SSRIs) for reducing aggression in conduct disorder. In a 6-week open study, citalopram (mean 27 mg/d) reduced impulsive aggression in 12 children with mixed diagnoses, as measured by the modified OAS,13 Child Behavior Checklist, and CGI.24
Recommendation. Use caution when prescribing SSRIs to aggressive youth, as these drugs may contribute to aggression in some mood-disordered children. More evidence of SSRIs’ safety and efficacy in this population is needed.
- Overt Aggression Scale. In: Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsiveaggressive behavior. J Neuropsychiatry 1991;3(2):S44-S51.
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Citalopram • Celexa
- Chlorpromazine • Thorazine
- Clonidine • Catapres
- Phenytoin sodium • Dilantin
- Divalproex • Depakote
- Guanfacine • Tenex
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Disclosure
Dr. Malone receives research support from Pfizer Inc. and Eli Lilly and Co. and is a consultant to Janssen Pharmaceutica.
Dr. Delaney is a consultant to Shire Pharmaceuticals.
Dr. Sheikh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Prescribing psychoactive medications for children and adolescents American Academy of Child and Adolescent Psychiatry policy statement, adopted Sept. 20, 2001. Available at:http://www.aacap.org/publications/policy/ps41.htm Accessed Jan. 15, 2004.
2. Pappadopulos E, MacIntyre JC, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145-61.
3. Hollander E, Tracy KA, Swann AC, et al. Divalproex in the treatment of impulsive aggression: efficacy in Cluster B personality disorders. Neuropsychopharmacology 2003;28:1186-97.
4. Physician’s Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.
5. Aman MG, DeSmedt G, Derivan A, et al. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry 2002;159:1337-46.
6. Snyder R, Turgay A, Aman M, et al. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
7. Findling RL, McNamara NK, Branicky LA, et al. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry 2000;39:509-16.
8. Malone RP, Maislin G, Choudhury MS, et al. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry 2002;41(2):140-7.
9. Sheard MH, Marini JL, Bridges CI, Wagner E. The effect of lithium on impulsive aggressive behavior in man. Am J Psychiatry 1976;133(12):1409-13.
10. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34:445-53.
11. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000a;57(7):649-54.
12. Yudofsky SC, Silver JM, Jackson W, et al. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143:35-9.
13. Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsive aggressive behavior. J Neuropsychiatry 1991;3:S44-S5.
14. Malone RP, Delaney MA, Gifford C. Adverse events during lithium treatment in children varies by setting. Miami Beach, FL: American Academy of Child and Adolescent Psychiatry annual meeting, 2003.
15. Rifkin A, Karajgi B, Dicker R, et al. Lithium treatment of conduct disorders in adolescents. Am J Psychiatry 1997;154:554-5.
16. Klein RG. Preliminary results: lithium effects in conduct disorders. New Orleans: American Psychiatric Association annual meeting, 1991.
17. Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17-25.
18. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment. New York: Marcel Dekker, 2003b;331-49.
19. Donovan SJ, Stewart JW, Nunes EV, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000;157:818-20.
20. Steiner H. A randomized clinical trial of divalproex sodium in conduct disorders. J Clin Psychiatry (in press).
21. Isojarvi JT, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:579-84.
22. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073-86.
23. Conner DF, Barkley RA, Davis HT. A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 2000;39:15-25.
24. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;886-94.
25. Armenteros JL, Lewis JE. Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study. J Am Acad Child Adolesc Psychiatry 2002;41:522-9.
1. Prescribing psychoactive medications for children and adolescents American Academy of Child and Adolescent Psychiatry policy statement, adopted Sept. 20, 2001. Available at:http://www.aacap.org/publications/policy/ps41.htm Accessed Jan. 15, 2004.
2. Pappadopulos E, MacIntyre JC, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry 2003;42(2):145-61.
3. Hollander E, Tracy KA, Swann AC, et al. Divalproex in the treatment of impulsive aggression: efficacy in Cluster B personality disorders. Neuropsychopharmacology 2003;28:1186-97.
4. Physician’s Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.
5. Aman MG, DeSmedt G, Derivan A, et al. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry 2002;159:1337-46.
6. Snyder R, Turgay A, Aman M, et al. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
7. Findling RL, McNamara NK, Branicky LA, et al. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry 2000;39:509-16.
8. Malone RP, Maislin G, Choudhury MS, et al. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry 2002;41(2):140-7.
9. Sheard MH, Marini JL, Bridges CI, Wagner E. The effect of lithium on impulsive aggressive behavior in man. Am J Psychiatry 1976;133(12):1409-13.
10. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995;34:445-53.
11. Malone RP, Delaney MA, Luebbert JF, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000a;57(7):649-54.
12. Yudofsky SC, Silver JM, Jackson W, et al. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143:35-9.
13. Coccaro EF, Harvey PD, Kupsaw-Lawrence E, et al. Development of neuropharmacologically-based behavioral assessments of impulsive aggressive behavior. J Neuropsychiatry 1991;3:S44-S5.
14. Malone RP, Delaney MA, Gifford C. Adverse events during lithium treatment in children varies by setting. Miami Beach, FL: American Academy of Child and Adolescent Psychiatry annual meeting, 2003.
15. Rifkin A, Karajgi B, Dicker R, et al. Lithium treatment of conduct disorders in adolescents. Am J Psychiatry 1997;154:554-5.
16. Klein RG. Preliminary results: lithium effects in conduct disorders. New Orleans: American Psychiatric Association annual meeting, 1991.
17. Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17-25.
18. Malone RP, Delaney MA. Psychopharmacologic interventions in children with aggression: neuroleptics, lithium, and anticonvulsants. In: Coccaro EF (ed). Aggression: assessment and treatment. New York: Marcel Dekker, 2003b;331-49.
19. Donovan SJ, Stewart JW, Nunes EV, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000;157:818-20.
20. Steiner H. A randomized clinical trial of divalproex sodium in conduct disorders. J Clin Psychiatry (in press).
21. Isojarvi JT, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:579-84.
22. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073-86.
23. Conner DF, Barkley RA, Davis HT. A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr 2000;39:15-25.
24. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;886-94.
25. Armenteros JL, Lewis JE. Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study. J Am Acad Child Adolesc Psychiatry 2002;41:522-9.