in Children and Adolescents - Semantic Scholar

Pharmacotherapy for Aggression

in Children and Adolescents Adelaide S. Robb, MD

A

Adelaide S. Robb, MD, is Associate Professor, Psychiatry and Pediatrics, The George Washington University School of Medicine, Children’s National Medical Center, Washington, DC. Address correspondence to: Adelaide S. Robb, MD, The George Washington University School of Medicine, Children’s National Medical Center, 111 Michigan Avenue, NW Washington, DC 20010; fax: 202-476-5898; or e-mail: [email protected]. Dr. Robb has disclosed the following relevant financial relationships: Bristol-Myers Squibb, Eli Lilly, Forest, McNeil, Otsuka: Member of Advisory Board; Lundbeck: Consultant; Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Otsuka, Pfizer, National Institute of Child Health and Human Development (NICHD), Sepracor, and Supernus; Research Grant Recipient; Epocrates: Royalties for column; and Bristol-Myers Squibb, Eli Lilly, Forest, and McNeil: Member of Speakers’ Bureau. doi: 10.3928/00485713-20100330-10

PSYCHIATRIC ANNALS 40:4 | APRIL 2010

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ggression is a behavior that is hardwired in individuals as part of the fight or flight response to a perceived threat. Aggression can be a normal reaction to a severe stress or threat, or it can be maladaptive. Children and adolescents can be aggressive

because they perceive things as threatening or violent, whether they are truly violent or not. For some, they have learned to perceive even benign stimuli in their environment as threatening and react to those threats with aggression. Maladaptive aggression accounts for one of the most frequent referrals to child psychiatric clinics.1 Aggression can be maladaptive based on duration of symptoms, frequency, intensity, or severity of the aggression in response to the level of the precipitant. It may even occur without any notable cause in the environment, as

in a child who explodes for “no reason.” These children may not cease the aggression, even with intervention by adults, and often misread social cues in the environment from peers and adults. Aggressive children may see negative emotions, while non-aggressive peers perceive positive emotions, as demonstrated by McClure et al, when presented with “neutral” sample facial expressions.2 Recent scientific understanding of aggression has split the aggression seen in children and adolescents into two main subcategories: impulsive (reactive) ag-

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gression (IA) and proactive aggression (PA).3 In IA, the person displaying aggression becomes aggressive in response to a situation. This type of aggression is usually based in fear and impulsive in nature, not preplanned, and easily observed by those in the child’s life. In PA, the person premeditates aggressive behavior in a “cold and calculating” fashion. Such aggression is seen in some bullies and may be used to gain rewards or impose the child’s will on others. The IA is frequently accompanied by negative emotions, including guilt and remorse after the event, as is often seen in clinic populations, while PA can elicit positive feelings in the aggressor and is more often seen in delinquent groups.4 Children with IA have early difficulties with peers and problem-solving skills, and up to 21% have a history of physical abuse. As these IA children progress through school, they have more severe psychopathology, including varying Axis I disorders. In several studies of large cohorts, children with IA account for 18% of all child and adolescent psychiatry visits, and up to 40% receive two or more medications.5,6 The most severe form of aggression is violence, and 18- to 24-year-old men tend to have the highest crime and murder rates as the most severe expression of aggressive behavior.7 This review of the pharmacologic treatment of aggression will focus on the treatment of IA. It will begin with evaluation of aggression and the use of rating scales. The next section will briefly examine non-pharmacologic interventions, which should be done as part of a multi-modal treatment plan for the child with IA. IA is frequently seen as a manifestation of an Axis I disorder, and this review covers the treatment of IA associated with the most common Axis I diagnoses. The article will also cover two important consensus documents that propose guidelines for treatment of IA in hospitalized youth and the future of pharmacologic studies for IA across diagnoses.

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EVALUATION AND RATING SCALES The first step in evaluating a child or teenager who presents with aggression is to obtain a detailed psychiatric evaluation, including psychiatric and medical history, previous psychiatric treatment, family history, and psychosocial stressors, including abuse, bullying, and other traumatic events. A good description of the aggressive event and the time course is crucial. Was this the first time

A good description of the aggressive event and the time course is crucial. the child acted in this way? Has the child been aggressive before this time? Was the aggression verbal, physical, against people or property? How long did the event last? Was there any build up before the event? After the child calmed down, how did he act, including expressions of guilt and remorse? It is important to interview the parents and child, and obtain collateral information (after obtaining a release of information) from school and other settings where the child has exhibited aggression. When interviewing the child, it may take more than one visit to secure the child’s trust, so he or she can tell you what it feels like when selfcontrol slips. If you can help the child identify the early signs of impending aggression, you may subsequently be

able to intervene with psychotherapeutic modalities to prevent future potential aggressive events. In an article that presented an overview of IA in various child psychiatric disorders, Jensen and colleagues developed a consensus report calling for accurate descriptions, rating scales, and new treatment trials.8 Rating scales used in the evaluation of aggression can help to characterize and quantify the IA, as well as provide a baseline of symptoms before treatment. General psychometric instruments that capture aggression as one of the symptoms on the broader scale include the Young Mania Rating Scale (YMRS), General Behavior Inventory Parent Version (P-GBI), Child Behavior Checklist (CBCL), Aberrant Behavior Checklist (ABC), and Nisonger Child Behavior Rating Form (NCBRF). Each of these instruments has an irritability, aggression, or conduct subscale as part of the overall rating scale. Other instruments are designed specifically to capture aggression as the main focus of the instrument, including the Modified Overt Aggression Scale (MOAS) and the Rating of Aggression Against People and/or Property (RAAPPS).9,10 In psychopharmacologic trials for the treatment of aggression in youth with IA, some or all of these rating scales may be used to evaluate the severity of aggression and as the primary outcome measure to quantify change with an intervention. The initial interventions, before pharmacologic management, are psychotherapy and psychoeducation as described in the next section. PSYCHOTHERAPEUTIC MODALITIES Psychotherapeutic interventions, such as hospitalization and milieu treatment alone, can markedly reduce aggressive behavior in as many as 50% of youth.11,12 Other psychosocial interventions found to be helpful include token economies, training in anger management, problem solving and social skills, and parent train-


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ing (with good communication between the school and home). Several excellent reviews cover psychosocial interventions for aggression and for conduct disorder in more detail.13,14 PHARMACOLOGIC MANAGEMENT OF AGGRESSION Because IA is usually seen as a symptom of an underlying Axis I disorder, this review examines the pharmacologic interventions by major diagnostic categories in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. In an analysis of youth with IA, a consensus group found that between 50% and 90% of youth with attentiondeficit/hyperactivity disorder (ADHD), unipolar depression, and bipolar disorder had medium to high levels of impulsive aggression, compared with 10% of youth without an Axis I diagnosis, demonstrating that aggression is seen across categories of Axis I disorders.8 A variety of psychotropic agents have been described in the literature as useful in the treatment of IA in youth with psychiatric disorders, including typical and atypical antipsychotics, anticonvulsants, anxiolytics, alpha-agonists, beta-blockers, sedatives, selective serotonin reuptake inhibitors, and stimulants.1,15 Disruptive Behavioral Disorders Disruptive behavioral disorders include ADHD, oppositional defiant disorder (ODD), and conduct disorder (CD). These disorders can occur separately or in combination with each other and are frequently associated with aggressive behavior. In the Multimodal Treatment Study of Children with ADHD (MTA), 44% of children who had aggression at baseline in the medication or medication plus therapy groups remained significantly symptomatic after 14 months of treatment. Although this number seems high, it also indicates that 56% of those with aggression at baseline were not significantly symptomatic with aggression


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TABLE.

Evidence for Efficacy of Positive Trials Using Medication in Aggression in Child Psychiatric Disorders Medication

ADHD +/- ODD/CD

ODD/CD

Stimulant

DBPC

DBPC

Atomoxetine

DBPC

Guanfacine XR

DBPC

Autism

Bipolar Disorder

DBPC

Clonidine

OLT

B-blockers

DBPC, OLT

Lithium

DBAC, DBPC

DBAC

Valproic acid

DBPC

DBAC

Carbamazepine

DBPC

Molindone

DBAC

Haloperidol

DBAC

Aripiprazole Risperidone

OLT AT

Olanzapine Quetiapine Ziprasidone

OLT

DBPC, FDAA

DBPC

DBPC, FDAA

DBPC

OLT

DBPC

OLT

DBPC

OLT

DBPC

ADHD=attention-deficit/hyperactivity disorder; ODD=oppositional defiant disorder; CD=conduct disorder; DBPC=double-blind, placebo-controlled trial; OLT=open label trial; AT=augmentation trial; DBAC=double-blind active comparator trial; FDAA=Food and Drug Administration approved for aggression

after the study interventions; this comprised 26% of all children in the MTA trial.16 One trial showed that children with ADHD and IA who are already being treated with a stimulant may respond to augmentation pharmacotherapy with risperidone.17 Other trials of children with ADHD and comorbid ODD/CD have shown that children may need higher doses of stimulants or atomoxetine to achieve remission of their ADHD and ODD/CD symptoms.18-20 In successful studies of conduct disorder, investigators have used clonidine, lithium, haloperidol versus lithium (both were effective), molindone, and aripiprazole.10,21-24 An open-label trial of ADHD and conduct disorder using clonidine at a dose of 0.4 mg/day showed improvement with reductions on the RAAPP and mild side effects.10 Other, more recent trials, include a successful study of quetiapine in the treatment of conduct disorder and guanfacine extended-release in the treatment of conduct disorder.25,26 The

practice parameters for the treatment of conduct disorder and aggression in inpatients have a variety of recommendations that address behavioral and pharmacologic recommendations to treat the aggression seen with conduct disorder in outpatient and inpatient settings.27,28 Autism and Pervasive Developmental Disorders Aggression in autism and patients with subaverage IQ is a serious problem that can disrupt life at home and jeopardize placement in the child’s educational setting. It is this aggression that frequently precipitates psychiatric hospitalization for children with these developmental disabilities. Medication trials for aggression in autism have included typical and atypical antipsychotic drugs, serotonergic drugs, naltrexone, alpha-agonists, beta-blockers, lithium, and anticonvulsants.29 Many of these trials have been positive and provide empiric support for the treatment of ag-


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SIDEBAR.

TRAAY Recommendations42 1. 2. 3. 4. 5.

6. 7.

8. 9. 10. 11. 12.

13. 14.

Conduct a diagnostic interview. Assess current treatment effects. Begin with psychosocial and psychoeducational treatments. Treat the primary Axis I disorder with its first-line treatment. Use an atypical antipsychotic (not a typical antipsychotic) for the aggression. Use a conservative dosing strategy. Use crisis management techniques before emergency treatment of aggression. Avoid using PRN medications to control behavior. Assess adverse effects routinely. Ensure an adequate trial before switching medications. After a failed trial of one atypical antipsychotic, try a second one. For a partial response, consider adding a mood stabilizer to the atypical antipsychotic. If non-response to polypharmacy, consider tapering one medication. If remission of symptoms for > 6 months, consider tapering the antipsychotics.

gression. The irritability subscale of the ABC has been used as the primary outcome measure in a series of recent clinical trials of risperidone and aripiprazole to treat aggression and irritability seen in autism. Both drugs have subsequently been FDA approved for the treatment of irritability and aggression associated with autism. Risperidone is approved for the treatment of children 5 to 16 years with autism and irritability.30 The dose should begin at 0.25 mg daily and can be titrated up by 0.25 mg every 2 weeks to a maximum dose of 1 mg for children weighing 15 to 20 kg; 2.5 mg if the child is 20 to 45 kg; and 3 mg if the child is more than 45 kg. In children more than 20 kg, the dose may start at 0.25 mg b.i.d and go up by 0.5 mg every 2 weeks. In 2009, the FDA-approved aripiprazole at


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doses of 2 to 15 mg to treat the irritability associated with autism in children 6 to 17 years. This approval was based on a flexible-dose study of aripiprazole versus placebo in 98 children with autism and a larger fixed-dose study of 218 children with autism.31,32 These two medications have the only FDA approvals for the treatment of aggression in any psychiatric disorder in childhood. A series of additional studies used risperidone to treat aggression with and without ADHD/ODD/CD in children with subaverage IQ in short-term double-blind studies and long-term open-label studies. Risperidone was effective in the treatment of aggression in these very large trials.33-35 Dosing of risperidone in these studies ranged from 0.02 to 0.06 mg/kg/d and average daily doses were 1.5 mg/d. Common side effects included somnolence in approximately one-third of youth and weight gain beyond that attributable to normal growth. Based on the extensive trials in this population, risperidone is the first option for treating aggression in the developmentally delayed population, followed by aripiprazole. Other atypical antipsychotics (olanzapine, quetiapine, and ziprasidone) have also been evaluated for aggression in this population but are not currently FDA approved for this indication. These positive studies have been small openlabel trials, and none has been a larger placebo-controlled trial. Bipolar Disorder Bipolar disorder frequently has irritability and aggression as part its symptom cluster. A large pediatric trial of lithium and valproic acid measured IA with the YMRS and P-GBI. The trial demonstrated that IA was present in a subset of youth. It also found a tendency to respond less well to treatment with the two mood stabilizers than those without IA.36,37 In all of the registration trials for pediatric bipolar disorder using atypical antipsychotic medications, compared

with placebo, the antipsychotic medications led to a significant reduction in aggressive symptoms on the YMRS. However, these medications are indicated for the treatment of bipolar disorder mixed or manic episodes, not the “treatment of aggression” in bipolar disorder. The Table (see page 233) provides a summary of the different disorders and types of effective medication. RECOMMENDATIONS FROM CONSENSUS GROUPS Two different groups approached the concept of IA in the field of child psychiatry and gave consensus recommendations about medication and treatment options and future research directions. The authors of the Treatment Recommendations for the use of Antipsychotics for Aggressive Youth (TRAAY) reviewed the literature, to date, on the pharmacologic treatment of aggression in youth and discussed agents commonly used to treat aggression in youth.38 The authors note haloperidol, pimozide, clozapine, olanzapine, quetiapine, and risperidone are all effective in the treatment of aggression. The studies were conducted with patients diagnosed with disorders ranging from conduct disorder and explosive aggression to tic disorders. Primary side effect concerns included weight gain, lipid, glucose, and insulin issues, as well as medication-specific side effects, such as agranulocytosis and seizures with clozapine, and QTc prolongation with ziprasidone. Their review noted that stimulants could improve the ADHD-associated aggression and the core symptoms of ADHD. Lithium and divalproex sodium were successful in treating aggression in conduct disorder, while carbamazepine was not successful in reducing aggression in conduct disorder.21,39,40 A review of 31 beta-blocker studies revealed they were effective in reducing aggression in a variety of psychiatric disorders in children with and without developmental disabilities, most frequently as an adjunctive


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medication.41 Side effects on beta-blockers can include sedation, hypotension, dizziness, bradycardia, bronchoconstriction, hypoglycemia, and possible alterations in growth hormone levels. In a second article on the TRAAY consensus meeting, the experts set a series of recommendations on when to use atypical antipsychotics for aggression in youth.42 They had a series of 14 recommendations for treatment of individuals with antipsychotics for aggression (see Sidebar, page 234). They can serve as a solid set of guidelines to inform clinicians before instituting treatment of aggression with antipsychotics or other medications. Clinicians are encouraged to move sequentially through the steps, rather than going immediately to medication. Using such a measured approach helps clinicians avoid overmedicating and polypharmacy in children with aggression. THE NEXT STEP The second consensus group was involved in assessing the state of the science in studying IA across the diagnostic categories in child psychiatry.8 They stated that the field was ready to study IA as a primary target of pharmacotherapy rather than a symptom of the primary Axis I disorder. They based their recommendations on the previous trials in the field and the need for better studies of IA. An extensive series of openlabel and double-blind trials of various psychotropic agents for the treatment of aggression over the past 15 years has led to the approval of only two medications by the FDA to treat aggression, which include aripiprazole and risperidone for the treatment of irritability in autism. No other drugs are approved for the treatment of irritability or aggression, and none is approved outside the diagnosis of autism. This lack of approved treatments persists, despite evidence of clinically significant irritability with a variety of Axis I disorders and knowledge that high levels of aggression in an Axis


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I disorder means a patient is less responsive to standard treatment. The consensus report on IA is asking for the field to consider testing drugs for aggression as a symptom across diagnoses.8 The group wants to use existing and new measures to examine medications in prospective randomized trials assessing aggression across diagnoses, and, as appropriate, to label other medications for the treatment of aggression outside the diagnosis of autism. Treatment of aggression could allow children to remain in their homes and schools and not in more restrictive settings. As we advance in the field of pediatric psychopharmacology, being able to optimally treat the primary diagnosis and the comorbid aggressive symptoms will allow clinicians to provide more patients a chance to achieve remission, rather than just a reduction in symptoms. That change would be an important advance in the treatment of children with psychiatric illness. REFERENCES 1. Connor DF. Aggression and Antisocial Behavior in Children and Adolescents: Research and Treatment. New York: The Guilford Press 2002. 2. McClure EB, Pope K, Hoberman AJ, Pine DS, Leibenluft E. Facial expression recognition in adolescents with mood and anxiety disorders. Am J Psychiatry. 2003;160(6):1172-1174. 3. Donovan SJ, Nunes EV, Stewart JW, Ross D, Quitkin FM, Jensen PS, Klein DF. “Outer-directed irritability”: a distinct mood syndrome in explosive youth with a disruptive behavior disorder? J Clin Psychiatry. 2003;64(6):698-701. 4. Connor DF, Steingard RJ, Cunningham JA, Anderson JJ, Melloni RH Jr. Proactive and reactive aggression in referred children and adolescents. Am J Orthopsychiatry. 2004;74(2):129-136. 5. Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry. 2006;63(6):679-685. 6. Pappadopulos 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. 7. Stringham P. Violence and men’s health. Prim Care. 2006;33(1):187-197, x. 8. Jensen PS, Youngstrom EA, Steiner H, et al. Consensus report on impulsive aggression

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35. Croonenberghs J, Fegert JM, Findling RL, De Smedt G, Van Dongen S; Risperidone Disruptive Behavior Study Group. Risperidone in children with disruptive behavior disorders and subaverage intelligence: a 1-year, open-label study of 504 patients. J Am Acad Child Adolesc Psychiatry. 2005;44(1):64-72. 36. Findling RL, McNamara NK, Gracious BL, et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry. 2003;42(8):895-901. 37. Findling RL, McNamara NK, Youngstrom EA, et al. Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(5):409-417. 38. Schur SB, Sikich L, Findling RL, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review. J Am Acad Child Adolesc Psychiatry. 2003;42(2):132-144. 39. Donovan SJ, Stewart JW, Nunes EV, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebocontrolled crossover design. Am J Psychiatry. 2000;157(5):818-820. 40. Cueva JE, Overall JE, Small AM, Armenteros JL, Perry R, Campbell M. Carbamazepine in aggressive children with conduct disorder: a doubleblind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1996;35(4):480-490. 41. Connor DF. Beta blockers for aggression: a review of the pediatrie experience. J Child Adolesc Psychopharmacol. 1993;3(2):99-114. 42. Pappadopulos E, Macintyre Ii 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):145-161.


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