Atypical antipsychotic medications in the management of disruptive behaviors in children: Safety guidelines and recommendations

Clinical Psychology Review 31 (2011) 465–471

Contents lists available at ScienceDirect

Clinical Psychology Review

Atypical antipsychotic medications in the management of disruptive behaviors in children: Safety guidelines and recommendations Cliff McKinney a,⁎, Kimberly Renk b a b

Mississippi State University, United States University of Central Florida, United States

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 3 June 2010 Received in revised form 4 November 2010 Accepted 10 November 2010 Available online 18 November 2010

Use of atypical antipsychotic medications (AAMs) in the treatment of Disruptive Behavior (DB) in children and adolescents has increased dramatically worldwide. However, with exception of using risperidone (i.e., for the management of irritability associated with Autism, manic and mixed episodes associated with Bipolar I Disorder, and Schizophrenia) and aripiprazole (i.e., for manic and mixed episodes associated with Bipolar I Disorder and Schizophrenia), the Food and Drug Administration (FDA) has not approved the use of AAMs in children and adolescents. Although research on use of these medications in children and adolescents has increased, mechanisms of action and long-term outcomes remain poorly understood or unknown. Particularly concerning is that use of these medications in children and adolescents may impact cognitive, social, and physical development, as side effects may interfere with activities in their educational setting, peer networks, and recreational settings. Overall, AAMs frequently are prescribed off label, control DB through sedation rather than targeting actual causes of DB, and lead to many negative side effects with unknown long-term effects. Reconsidering the use of AAMs in managing DB is encouraged strongly. © 2010 Elsevier Ltd. All rights reserved.

Keywords: Atypical antipsychotic medication Children Adolescent Disruptive behavior

Contents 1. 2.

Introduction . . . . . . . . . . . . . Previous research . . . . . . . . . . 2.1. Risperidone . . . . . . . . . 2.2. Olanzapine and aripiprazole . . 2.3. Medications in general . . . . 3. Safety concerns and recommendations References . . . . . . . . . . . . . . . .

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1. Introduction Despite concerns about tolerability and long-term effects, traditional antipsychotic medications are used for the treatment of a variety of psychotic and non-psychotic conditions in children and adolescents (Sivaprasad, Hassan, & Handy, 2006). In more recent times, atypical antipsychotic medications (AAMs) are being used more frequently due to the lower occurrence of negative side effects with these medications relative to traditional antipsychotic medications (Croarkin, Emslie, & ⁎ Corresponding author. Mississippi State University, Department of Psychology, P.O. Box 6161, Mississippi State, Mississippi 39762, United States. Tel.: +1 662 325 3782; fax: +1 662 325 7212. E-mail address: [email protected] (C. McKinney). 0272-7358/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.cpr.2010.11.005

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Mayes, 2008; Erdogan et al., 2008; Sivaprasad et al., 2006; Zito, Safer et al., 2008). In one study (Sivaprasad et al., 2006), a postal survey in a region of the United Kingdom was sent to 57 community and inpatient psychiatrists in 2003 so that an estimate of their use of AAMs could be obtained for the previous year. Of the 39 respondents, 95% of them reported prescribing AAMs to children and adolescents, and 65% reported prescribing these medications for non-psychotic conditions (Sivaprasad et al., 2006). Similarly, Zito, Safer et al. (2008) noted increases in the use of AAMs in the Netherlands and Germany. These results suggest that, in fact, AAMs are widely used with children and adolescents. Similar results are noted in the United States as well. Another study (Staller, Wade, & Baker, 2005) examined the current prescribing patterns of outpatient child psychiatrists in central New York. The files

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of children and adolescents who ranged in age from 1- to 18-years from eight outpatient locations in central New York and who were seen for appointments on one day in 2002 were reviewed (N = 1292). Findings indicated that 74% of these children and adolescents received psychotropic medication and that 50% received two or more of these medications. The most commonly prescribed medications included stimulants, antidepressants, antipsychotics, alpha-agonists, and mood stabilizers. Further, these children and adolescents were diagnosed most commonly with Attention-Deficit/Hyperactivity Disorder, other Disruptive Behavior Disorders (DBD), Anxiety Disorders, and Depressive Disorders. Of the children and adolescents who were prescribed antipsychotic medications, 77% did not have a diagnosis of a Psychotic Disorder (Staller et al., 2005). Olfson, Blanco, Liu, Moreno, and Laje (2006) also examined trends in the use of antipsychotic medications in conjunction with outpatient visits across the United States. This study found that office visits by youth that included antipsychotic medications increased from approximately 201,000 in 1993 to 1,224,000 in 2002. From 2000 to 2002, male visits (1913 per 100,000) involving treatment with antipsychotic medications were significantly higher in number than female visits (739 per 100,000). In addition, visits for White, non-Hispanic youth (1515 per 100,000) were significantly higher than those for youth from other ethnic groups (426 per 100,000). Overall, this study found that 9.2% of all mental health visits and 18.3% of visits to psychiatrists included treatment with antipsychotic medications. From 2000 to 2002, 92.3% of visits involving treatment with antipsychotic medications utilized AAMs. Diagnoses that were treated in these sessions were varied and included DBDs (37.8%), Mood Disorders (31.8%), Pervasive Developmental Disorders (PDD) or Intellectual Disability (17.3%), and Psychotic Disorders (14.2%; Olfson et al., 2006). This study concluded that a sharp national increase in the use of AAMs for the treatment of children and adolescents in office-based medical practice has occurred, especially for DBDs and other nonPsychotic Disorders. These increases may be particularly concerning as the basis of support for the use of AAMs is limited to short-term safety and efficacy (Olfson et al., 2006). Thus, partly due to improved tolerability and efficacy profiles of AAMs, these medications are being used increasingly to treat a growing number of children and adolescents presenting with a variety of disorders, including Disruptive Behavior (DB), Mood, Developmental, Psychotic, and Eating Disorders (Croarkin et al., 2008; Erdogan et al., 2008; Findling, 2003; Findling, Aman, Eerdekens, Derivan, & Lyons, 2004; Mehler-Wex, Romanos, Kirchheiner, & Schulze, 2008; Stigler & McDougle, 2008; Ritchie & Norris, 2009; Troost et al., 2005; Zito, Safer et al., 2008). Although AAMs are indicated in the treatment of adults only, they often are used in offlabel treatments in the United States to address the DB exhibited by children and adolescents (Findling, 2003). It is not uncommon for different medications to be used off-label in the treatment of children and adolescents who are exhibiting emotional and behavioral symptoms. In fact, 50 to 75% of pediatric medications are prescribed off label (Zito, Derivan, Kratochvil, Safer, Fegert, & Greenhill, 2008). There are two exceptions to the off-label medication use of AAMs. These exceptions include the FDA approved usage of risperidone in the treatment of irritability associated with Autism for children who range in age from 5- to 16-years, in the treatment of manic and mixed episodes associated with Bipolar I Disorder in children who range in age from 10- to 17-years, and in the treatment of Schizophrenia in children who range in age from 13- to 17-years. The second exception includes the FDA approved usage of aripiprazole in the acute treatment of manic and mixed episodes of Bipolar I Disorder in children who range in age from 10- to 17-years and in the treatment of Schizophrenia in children who range in age from 13- to 17-years (Croarkin et al., 2008; Greenaway & Elbe, 2009; Scott & Dhillon, 2008; Stigler & McDougle, 2008). AAMs also are used often to treat children and adolescents with other PDDs, DBDs, Eating Disorders, Movement Disorders, other Mood Disorders, Anxiety Disorders, and other

Psychotic Disorders, however (Findling, 2003; Greenaway & Elbe, 2009; Mehler-Wex et al., 2008; Ritchie & Norris, 2009; Stigler & McDougle, 2008). Overall, the most common reason that AAMs are prescribed to children and adolescents appears to be for managing “pernicious, pervasive, persistent aggression in the context of DBDs” (Findling, 2003, p. 10). Although both traditional antipsychotics and AAMs may have some utility in treating some DB, as well as other disorders, exhibited by children and adolescents, this usage is problematic. Children and adolescents are not smaller adults and may not respond to medications in a similar manner as adults. For example, use of tricyclic antidepressants has been shown to be safe and efficacious in treating adults with Depression, but use of these medications in children and adolescents has led to more adverse events (AE) and side effects than were noted in adult populations (Findling, 2003). A similar scenario may be playing out with AAMs as well. For example, children and adolescents appear to be at higher risk for sedation, weight gain, and Movement Disorders that are associated with extrapyramidal symptoms (EPS) as well as other adverse effects that are prompted by AAMs (Findling, 2003; Zito, Derivan, et al., 2008). Thus, before the real utility of AAMs can be determined, previous research examining the efficacy of AAMs in children and adolescents needs to be examined. 2. Previous research Despite growing use of AAMs in children and adolescents, the research informing such use is lacking (Findling, 2003). Although research in this area is fairly new, the use of antipsychotic medications in treating DB is not. These medications have been used over the past 20 (Croonenberghs et al., 2005) to 50 (Zito, Derivan, et al., 2008) years to treat DB. A majority of the research literature focuses on the use of risperidone in treating DB in children and adolescents; however, other medications including olanzapine, aripiprazole, quetiapine, ziprasidone, and others are starting to be examined as well. This research will be examined here. 2.1. Risperidone Risperidone is a potent postsynaptic dopamine and serotonin receptor blocker and is the most well studied AAM (Findling et al., 2004; Troost et al., 2005). The short-term efficacy of risperidone in managing behavioral problems associated with Autism Spectrum Disorders (i.e., PDDs) is well established (Troost et al., 2005). Risperidone is approved for use in a number of European countries (De Deyn & Buitelaar, 2006; Reyes, Olah, Csaba, Augustyns, & Eerdekens, 2006), and it has received FDA approval for treating irritability occurring in conjunction with Autism, for treating mania and mixed episodes that occur with Bipolar I Disorder, and for treating Schizophrenia. Much research has explored the effects of risperidone when used to treat DBDs in the short term as well. The effects of the long-term use of this medication are less well known, however (Troost et al., 2005). Risperdone is one of the better studied AAMs, with a number of the studies that have been completed for children and adolescents summarized here. For example, Troost et al. (2005) examined the use of risperidone for the treatment of Autism Spectrum Disorders over a 6-month period. A total of 36 children who ranged in age from 5- to 17-years, who were diagnosed with an Autism Spectrum Disorder, and who exhibited severe tantrums, aggression, or selfinjurious behavior started an eight-week open-label treatment trial with risperidone (i.e., with doses starting at 0.5 mg/day and increasing to 2.5 mg/day by day 29). Participants were seen every 4 weeks for assessment of efficacy, safety, and dose adjustments and were seen weekly during the discontinuation phase. Ratings included the Clinical Global Impression (CGI) scale of symptom change (completed by a clinician) and the irritability subscale of the Aberrant Behavior

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Checklist (ABC; completed by the parent and confirmed by a child psychiatrist). Baseline ratings were compared with endpoint changes with the two-sided Wilcoxon signed rank test. Further, relapse was defined as the occurrence of either a CGI rating of much worse or very much worse for 2 consecutive weeks and at least a 25% increase on the irritability subscale of the ABC. Responders to the treatment included 26 children who continued treatment for an additional 16 weeks, followed by a double-blind discontinuation consisting of either three weeks of taper followed by five weeks of placebo only or a continuation of risperidone. Excessive weight gain led to the removal of two participants during this period. This study found that risperidone, according to clinician, parent, and child psychiatrist ratings, was superior to placebo in preventing or delaying relapse, which was defined as a significant deterioration of symptoms. Relapse occurred in 3 of 12 patients who continued receiving risperidone versus 8 of 12 patients who had their use discontinued. Weight gain, increased appetite, anxiety, and fatigue were the most common side effects reported for these children. The Research Units on Pediatric Psychopharmacology Autism Network (2005) also examined the effects of risperidone in children who ranged in age from 5- to 17-years and who were diagnosed with Autism. This sample of children exhibited severe tantrums, aggression, and/or self-injurious behavior and had shown a positive response in an earlier eight-week trial. Participants received four months of openlabel treatment with risperidone starting at the established optimal dose (M = 1.96 mg/day) and then entered an eight-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Participants were seen every 4 weeks for 4 months for assessment of efficacy, safety, and dose adjustments and were seen weekly during the discontinuation phase. Ratings included the irritability subscale of the ABC — Community version (completed by the parent or primary caretaker and confirmed by clinical review) and the CGI severity scale (completed by the examining clinician). Participants who showed a 25% reduction on the irritability subscale of the ABC and a rating of much improved or very improved on the CGI improvement scale were classified as positive responders. Relapse was defined as a 25% increase on the irritability subscale of the ABC and a CGI improvement rating of much worse or very much worse for at least 2 consecutive weeks as rated by a blinded clinician. Findings indicated that positive effects of risperidone were maintained over the four-month period and that 62.5% of participants who were discontinued from risperidone experienced relapse compared with 12.5% of participants continuing risperidone treatment. Participants gained an average of 5.1 kg, five participants discontinued due to loss of efficacy, and one participant discontinued due to an AE. The 37.5% of participants who were discontinued from treatment and did not relapse indicated a degree of outcome variability. As a result, the article encouraged reducing and tapering dosages as well as incorporating the behavioral reinforcement of replacement behaviors during risperidone withdrawal. Such recommendations should be implemented with caution, however, as the risk for relapse in this study was high. Further, Findling et al. (2004) examined use of risperidone (i.e., with a mean dose of 1.5 mg/day) over 48 weeks in 107 children who ranged in age from 5- to 12-years and who exhibited severe DB and below average intelligence (i.e., the IQs of these children ranged from 36 to 84). Ratings included the conduct problem subscale of the Nisonger Child Behavior Rating Form (N-CBRF; completed by parents), the Visual Analog Scale for the Most Troublesome Symptom (VAS-MS), and the CGI disease severity index (completed by the investigator). These measures were used at baseline and at weeks 4, 12, 24, 36, and 48, and efficacy was determined by comparing baseline to endpoint. With use of risperidone, the most common AEs reported were somnolence (33%), headache (33%), rhinitis (28%), and weight gain (21%; i.e., with a mean increase of 5.5 kg, half of which was attributed to normal growth). In addition, transient and asymptomatic increases in prolactin levels were noted, but no significant

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changes in EPS or cases of tardive dyskinesia (TD) were reported. Overall, risperidone was associated with rapid, significant reductions of Conduct Problems in patients who were previously given placebo and resulted in long-term improvement in patients who were previously given risperidone. This study also indicated that there was an improvement in cognitive functioning, although this may have been due to practice effects in the administration of intellectual assessments, normal maturation, risperidone, or a combination of these factors. Further, it was difficult to assess the patients' level of cognitive improvement, as standardized norms were not available for this population. Croonenberghs et al. (2005) also examined the long-term safety and effectiveness of risperidone (i.e., with an average dose of 1.6 mg/day) in children who ranged in age from 5- to 14-years and who also exhibited below average intelligence (i.e., the IQ of these children ranged from 36 to 84) and DBDs. This study was conducted for one year across 32 sites in 12 countries in North America, Europe, and South Africa. Ratings included the N-CBRF, ABC, CGI, Child Symptom Inventory (CSI), and VAS-MS. The parent or caregiver completed the N-CBRF, CSI, VAS-MS, and the ABC and the clinician examined the participant and completed the CGI. Assessments for effectiveness were made at baseline, weekly during the first 4 weeks, and then monthly, and baseline was compared to endpoint. Findings of this study indicated that the use of risperidone in this population was generally safe and effective. Discontinuation due to AEs and insufficient response occurred in 9% and 4% of the participants in the study, respectively. Increases in prolactin levels also were noted but rarely resulted in discontinuation as these increases appeared to be transient reactions. Weight gain was a common reason for discontinuation; however, half of the weight gain experienced by the participants in this study was attributable to normal growth (Croonenberghs et al., 2005). In an extension of the previous study, Reyes, Olah, et al. (2006) examined effects of risperidone (with dosing determined on an individual basis based on tolerability and efficacy) in treating Hungarian children who ranged in age from 6- to 16-years and who were diagnosed with DBDs and below average intelligence (i.e., the IQs of these children ranged from 35 to 84) over a three-year period. Treatment efficacy was assessed by the investigator-rated CGI severity score, which was obtained pre-treatment, at extension study enrollment, and every 3 months. Beneficial effects noted within the first year of treatment were maintained over the two-year extension period. Few EPS and no cases of TD were reported, modest increases in body-mass indices were noted and partly attributable to normal growth, and most AEs were mild or moderate in severity. None of these AEs was considered probably or very likely related to the use of risperidone (Reyes, Olah, et al., 2006). Reyes, Buitelaar, Toren, Augustyns, and Eerdekens (2006) also examined the effects of risperidone (with dosages ranging from 0.25 to 1.5 mg/day based on weight and clinical judgment) on 527 children who ranged in age from 5- to 17-years and who lived in eight different countries. These children varied in their level of intellectual functioning (i.e., 190 participants had an IQ between 55 and 84, whereas 145 participants had an IQ over 84). These children were diagnosed with a DBD, however. Of these children, 192 had some issue that prevented them from being assigned randomly as part of the study (i.e., children who showed no initial [N = 52] or continued [N = 61] response to risperidone, experienced AEs [N = 12], were lost to follow-up [N = 20], withdrew their consent [N = 15], were noncompliant [N = 14], or had other reasons for discontinuing [N = 18]). The remaining 335 children were assigned randomly to a double-blind maintenance condition (N = 172) or placebo (N = 163) over a six-month period. The primary efficacy measure was time to symptom recurrence, which was defined as a deterioration of 2 or more points on the CGI severity scale or 7 or more points on the conduct problem subscale of the N-CBRF at two consecutive visits that were 6 to 8 days apart. Other measures included other N-CBRF subscales, the CGI change scale, and the VAS-MS, all measured

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biweekly during acute and continuation treatment and monthly during maintenance treatment. The time to symptom recurrence was significantly longer in patients who continued risperidone (119 days) relative to those who were switched to placebo (37 days). This study demonstrated that initial responders to risperidone benefit from its long-term use. Scott and Dhillon (2008) examined effects of risperidone in children and adolescents who ranged in age from 5- to 17-years and who were diagnosed with Autism during two eight-week randomized, double-blind trials (N = 101 and 55). Efficacy was assessed primarily by comparing irritability scores from baseline to endpoint as measured by the irritability subscale of the ABC (completed by the parent). Secondary efficacy measures included other subscales of the ABC (i.e., stereotypic behavior, lethargy/social withdrawal, hyperactivity/noncompliance; completed by the parent); the Ritvo-Freeman Real Life Rating Scale (used to assess repetitive behavior and impaired communication; completed by parents); the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; completed by a clinician); the Maladaptive Behavior Domain of the Vineland Adaptive Behavior Scales (completed by a clinician); the conduct problem, hyperactive, and overly sensitive subscales of the N-CBRF; and the score for hyperactivity on the VAS-MS. Irritability, stereotypic behavior, and hyperactivity were noted to decrease with the usage of the medication. AEs included somnolence, weight gain, increased prolactin, increased appetite, fatigue, upper respiratory tract infection, increased saliva, constipation, dry mouth, tremor, dystonia, and TD. Haas, Karcher, and Pandina (2008) conducted an open-label, oneyear extension study involving 232 participants who ranged in age from 5- to 17-years and who were exhibiting a DBD. A total of 169 (73%) participants completed the study, with the majority being males who had been diagnosed with Oppositional Defiant Disorder. Efficacy measures included the conduct problem subscale of the N-CBRF (completed by the caregiver), other N-CBRF subscales, CGI severity subscale (completed by a clinician), Children's Global Assessment Scale (CGAS; completed by a clinician), and the VAS-MS (completed by the parent). N-CBRF and CGI scores were obtained at baseline, week 2, and months 1, 2, 4, 6, 9, and 12, and endpoint. CGAS was obtained at baseline, month 12, and end point. The researchers noted a decrease in DB symptoms overall but also noted AEs (i.e., weight gain, EPS, increase in prolactin although typically not associated with an AE) in ten (4.3%) participants (Haas et al., 2008). With regard to comparisons of Risperdone with another type of treatment, Caldwell, Malterer, Umstead, and McCormick (2008) compared the effects of a psychosocial intervention (i.e., a cognitivebehavioral therapy intervention) coupled with risperidone (N = 60) to a comparison group who received the psychosocial intervention only (N = 69). Participants in this study were adolescents who ranged in age from 13- to 18-years and who were diagnosed with childhood onset Conduct Disorder. Clinical assessment variables included academic achievement (obtained from records of an admission school assessment using the Peabody Individual Achievement Test-Revised), a Conduct Disorder symptom checklist (based on criteria specified in the DSM-IV-TR and completed by clinical staff), intellectual functioning (obtained from previous records or from intelligence testing completed as part of the admission assessment using the Full Scale Intelligence Quotient from the Wechsler Intelligence Scale for Children-Revised), and the MJTC Behavioral Assessment System (a behavioral point program that provides a sensitive measure of treatment involvement and compliance completed by treatment staff and supervisor). Results indicated that the risperidone group showed significant improvement in interpersonal behavior and rule compliance compared to baseline and relative to the comparison group. The AEs that were noted in this study included somnolence (26%), weight gain (18%), increased appetite (17%), and constipation (14%). As a means of summarizing the research literature regarding the usage of Risperdone, De Deyn and Buitelaar (2006) reviewed 19 open-

label, double-blind studies investigating the effects of risperidone on agitation and aggression across the age span, including some of the studies mentioned above. De Deyn and Buitelaar (2006) provide tables summarizing various efficacy measures for the different studies, including the N-CBRF, ABC, and CGI. Results of this review indicated that the safety and tolerability of low-dose risperidone (with a dosage ranging from 0.75 to 3.5 mg/day) was good overall but that certain safety issues, such as somnolence and weight gain in children, should be noted. Thus, if AAMs were to be used in children and adolescents, this summary of the research suggested that risperidone may be a useful option when prescribed at a low dose.

2.2. Olanzapine and aripiprazole Olanzapine also has received recent attention as a treatment for DB. Masi et al. (2006) retrospectively examined the use of olanzapine (with a dosage ranging from 5 to 20 mg/day) in 23 adolescents who ranged in age from 11- to 17.2-years and who were diagnosed with severe Conduct Disorder. All participants were involved in concomitant non-pharmacological treatments. Measures of efficacy included the Modified Overt Aggression Scale (MOAS; administered by a clinician), the Aggression Questionnaire (AQ; completed by a clinician), the CGI severity and improvement scales, and the CGAS. Baseline and endpoint scores were obtained and compared. Fourteen of the 23 participants experienced a 50% reduction in DB. Further, these participants' impulse affective aggression (versus controlledpredatory aggression) served as a predictor of their treatment response. Handen and Hardan (2006) also conducted a prospective, openlabel study on the use of olanzapine (with a dosage ranging from 5 to 20 mg/day) over eight weeks with 16 adolescents who ranged in age from 13- to 17-years. These adolescents were diagnosed with a DBD and had below average intelligence (i.e., the IQs of these adolescents ranged from 36 to 79). Efficacy measures were obtained at baseline, weekly for the first 4 weeks, and at 2-week intervals for the last 4-week period. A primary caretaker (e.g., parent, group home staff member) served as an informant during each clinic visit and the prescribing physician conducted the outcome assessment at each study visit. The primary outcome measures included the ABC (completed by the informant), the Conners Parent Rating Scale (completed by the informant), and the CGI severity and improvement subscales (completed by the primary investigator at the time of each visit). With the use of olanzapine, significant decreases in irritability and hyperactivity were found in this sample. Four participants discontinued the study due to a worsening of their symptoms or the experience of serious side effects, however. The most common side effects were weight gain (M = 12.7 pounds) and increased prolactin levels, although no significant events related to increased prolactin occurred. With regard to aripiprazole, a review paper by Greenaway and Elbe (2009) reported that aripiprazole has been used to treat children and adolescents who range in age from 0- to 18-years and who have been diagnosed with Schizophrenia and Bipolar Disorder (both usages that are FDA approved). In addition, aripiprazole has been used offlabel for children and adolescents who are diagnosed with Movement Disorders and DBDs. The studies included in this review utilized various efficacy assessments, including the ABC, CGI, CY-BOCS, Overt Aggression Scale (OAS), and CGAS, among others. This review found that aripiprazole did not appear to have any cardiac or metabolic side effects. In contrast, children and adolescents were noted to experience EPS, akathisia, sedation, headache, and nausea while taking this medication, as well as having the possibility of experiencing TD. Given these findings, the usage of olanzapine and aripiprazole is not as well supported as the usage of risperidone.

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2.3. Medications in general Other studies examine medications more generally. For example, in one review paper examining a variety of different types of medication, Handen and Gilchrist (2006) examined the use of different psychotropic medications in children and adolescents who have intellectual disabilities. Medications reviewed in this paper included stimulants, antipsychotics (including risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole), antidepressants, mood stabilizers, and other drugs. Results indicated that children and adolescents who have intellectual disabilities respond similarly to these medications as nonclinical children and adolescents. In contrast, children and adolescents who have intellectual disabilities tend to have poorer response rates and a higher frequency of side effects. Thus, this review recommended that greater monitoring, lower dosages of medication, and slower dosage increases should be used generally for children and adolescents who have been diagnosed with intellectual disabilities. 3. Safety concerns and recommendations Given that parents are seeking AAMs as part of the treatments for DB in their children and adolescents and that medical professionals are willing to prescribe AAMs for DB in children and adolescents, it is clear that DB may cause of a number of problems for children and adolescents as well as for their caregivers, educators, and other individuals who interact with these children and adolescents. If left untreated, DBDs may lead to additional problems during critical periods of development (Findling et al., 2004). Further, DBDs are the most frequently diagnosed category of childhood disorders (Rey & Walter, 1999). Thus, finding effective and efficacious treatments for children and adolescents diagnosed with DBDs is paramount so that these children and adolescents may avoid future problems. Beyond the AAMs discussed thus far, many psychosocial interventions (e.g., parent management training, collaborative problem solving, parentchild interaction therapy, empathy and social skills training, promoting prosocial behavior and problem-solving skills) have been developed to address DBDs in normally developing children and have been validated extensively (Kazdin, 1995, 2007). A population that may be especially at risk for developing DB, however, is children who have below average intelligence and/or PDDs, as these children experience DB in up to 64% of cases (Reyes, Olah, et al., 2006). This high rate of DB coupled with the difficulty in applying psychosocial interventions in this population is a possible explanation that a majority of the research examining the use of AAMs in children, adolescents, and adults does so with individuals experiencing intellectual deficits or PDDs. Even with this difficult population, however, non-pharmacologic interventions are recommended as the first line of treatment (e.g., Early Intensive Behavioral Intervention for children with Autism; Eldevik et al., 2009). Nonetheless, future research typically is called for when there are unanswered questions. For example, the extant literature does not address adequately the long-term effects of AAMs for children and adolescents or the effects of AAMs on children and adolescents who are developing normally. Although the obvious argument may be to conduct more research to address these gaps in the current research literature, implementing future research on the usage of AAMs with children and adolescents, some of whom may not have the opportunity to assent, raises grave concerns. Consider the case of a 7-year-old boy involved in the foster care system in Florida described by Miller (2010). After death of this boy's mother, the state took custody of him in June 2008. Subsequently, the child was prescribed antipsychotic and antidepressant medications. In April 2009, the child hanged himself, prompting state legislators to propose a bill regulating the use of medications for children and adolescents involved in state care. Recommendations of the bill included requiring children and adolescents in state care to have guardians ad litem (i.e., volunteer lay

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guardians) or attorneys appointed to represent them and their interests, prohibiting children and adolescents in state care from being involved in clinical trials designed to determine the safety or efficacy of medications not approved by the FDA, requiring an independent medication review before psychiatric medications may be prescribed, and incorporating an overall treatment plan with a preference toward psychosocial treatments when children and adolescents in state care are prescribed psychiatric medications. The creator of the bill commented, “We're not going to just drug [youth] through their childhood and adolescence” (Miller, 2010). Although the above case may be a sensational AE of unknown causes, a plethora of AEs associated with AAMs have been documented. Even though the side effect profiles of AAMs are a gross improvement over traditional antipsychotics, it still must be understood that many negative side effects exist. In fact, AEs may be underreported by 80 to 95% (Elbe, 2009; Hazell & Shakir, 2006). Thus, actual occurrence of AEs may be much more considerable than that represented in the extant literature. Further, much of the research dismisses many AEs as not being severe or resolving upon discontinuation of the AAM. Although some side effects may not lead to AEs and some AEs may not be severe or may resolve when medication is stopped, unnecessary risks are being taken with children and adolescents and their development, particularly when the extant literature frequently supports the use of psychosocial or behavioral interventions as the first line of treatment. Overall, developmental concerns for children and adolescents with DB must be considered, as DB may interrupt normal development. Equally important, the impact of AAMs, as well as other medications, on developing children and adolescents also must be considered. One particularly concerning AE is Neuroleptic Malignant Syndrome (NMS), which is a rare iatrogenic reaction to antipsychotic medications that is not well understood and potentially fatal (Croarkin et al., 2008; Greenaway & Elbe, 2009; Neuhut, Lindenmayer, & Silva, 2009). Although debate exists over exact diagnostic criteria, symptoms may include “rigidity, fever, increased serum creatine phosphokinase levels, leukocytosis, autonomic instability, tachypnea, delirium, and diaphoresis” (Croarkin et al., 2008, p. 1158) as well as altered mental status and tachycardia (Neuhut et al., 2009). Croarkin et al. (2008) and Neuhut et al. (2009) reported contemporary incidence rates of NMS from 0.01 to 0.02% in adult populations but noted that there is a lack of information regarding child populations. In the review by Croarkin et al. (2008), 20 reported cases of NMS associated with the use of AAMs in the treatment of children and adolescents were found searching from 1991 to 2007. Neuhut et al. (2009) also found 20 cases of NMS searching from 1990 to 2008 in children aged 0 to 18 years. Other particularly concerning AEs include cardiac problems, ranging from tachycardia and QTc interval prolongation to cardiac arrest and death (Greenaway & Elbe, 2009; Ray, Chung, Murray, Hall, & Stein, 2009; Ritchie & Norris, 2009). Serious movement problems including EPS, dystonia, tremor, akathisia, and TD also are associated with AAMs (Correll & Kane, 2007; Greenaway & Elbe, 2009; Haas et al., 2008; Reyes, Olah, et al., 2006; Scott & Dhillon, 2008; Zito, Derivan, et al., 2008). Correll and Kane (2007) conducted a review on the association between AAMs and TD in children and adolescents. They reviewed ten studies including 783 children and adolescents who received risperidone, olanzapine, or quetiapine for an average of 329.6 days for a variety of disorders, including DBDs, Mood Disorders, Psychotic Disorders, and PDDs. In this review, three cases of TD were found (Correll & Kane, 2007). One of the most common AEs associated with AAMs is significant weight gain beyond that which is expected due to maturation. Nearly every study reported weight gain beyond maturation (Caldwell et al., 2008; Croonenberghs et al., 2005; Findling et al., 2004; Fraguas et al., 2008; Greenaway & Elbe, 2009; Haas et al., 2008; Handen & Hardan, 2006; Research Units on Pediatric Psychopharmacology Autism Network, 2005; Reyes, Olah, et al., 2006; Scott & Dhillon, 2008; Troost et al., 2005; Zito, Derivan, et al., 2008). Given increasing concerns

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regarding childhood obesity in today's society (e.g., childhood obesity is linked to numerous physical and psychological health outcomes), metabolic side effects may be particularly disconcerting (Fraguas et al., 2008). Other metabolic and hormonal AEs include increased appetite, nausea, vomiting, constipation, increased saliva, dry mouth, gastrointestinal bleeding, hyperglycemia, dyslipidemia, liver function changes, hyperprolactinemia, and hyperthyroidism (Coskun & Mukaddes, 2008; Erdogan et al., 2008; Fraguas et al., 2008; Greenaway & Elbe, 2009; Scott & Dhillon, 2008; Zito, Derivan, et al., 2008). Beyond these AEs, many other side effects also may occur. In addition to noted cases of edema (Akdag, Fettahoglu, & Ozatalay, 2009), sexual dysfunction (e.g., frequent penile erections; Wadoo & Chalhoub, 2009), headache (Greenaway & Elbe, 2009), upper respiratory tract infection (Scott & Dhillon, 2008), and epistaxis (Coskun & Mukaddes, 2008), many studies document the discontinuation of AAMs due to relapse, loss of efficacy, or worsening of symptoms (Croonenberghs et al., 2005; Handen & Hardan, 2006; Research Units on Pediatric Psychopharmacology Autism Network, 2005; Reyes, Buitelaar, et al., 2006; Troost et al., 2005). In fact, Reyes, Buitelaar, et al. (2006) noted that 21% of their sample (113 out of 527 youths) discontinued treatment due to the lack of initial or continued response to AAMs. Further, Handen and Hardan (2006) reported that 25% of their sample (four out of 16 youths) discontinued treatment due to worsening of symptoms or serious side effects. Finally, somnolence, fatigue, and lethargy are other documented AEs and appear to be the most frequent AE after weight gain (Caldwell et al., 2008; De Deyn & Buitelaar, 2006; Greenaway & Elbe, 2009; Scott & Dhillon, 2008; Troost et al., 2005). For example, the percentage of participants experiencing somnolence ranged from 26 to 78% (Caldwell et al., 2008; Greenaway & Elbe, 2009). This AE may be particularly important to consider given that somnolence, fatigue, and lethargy may be considered incompatible with DB. For example, the sleepier, more fatigued, and/or more lethargic children and adolescents are, the less likely that they are to have the energy to engage in DBs. Thus, AAMs may reduce DB through sedation rather than by targeting the actual causes of this behavior. In addition to the sedation hypothesis noted above, AAMs also affect serotonin, a neurotransmitter that is linked to aggression (Halperin et al., 2006; Janowsky, Shetty, Barnhill, Elamir, & Davis, 2004). If the mechanism of action for DB is related to serotonin, then perhaps medications such as Selective Serotonin Reuptake Inhibitors may have similar effects on DB without the side effects associated with AAMs. Even then, caution must be urged, as some antidepressants may be linked with increased rates of suicide in adolescents and have their own side effect profiles (Findling, 2003). At any rate, examining effects of medications, particularly AAMs, in children and adolescents must be done with extreme caution, if at all. For example, many psychosocial and behavioral interventions are highly effective, as already noted above. Even Conduct Disorder and Autism, disorders that are perceived traditionally to be difficult to treat, have treatments which are validated highly (Eldevik et al., 2009; Kazdin, 2007). In the event that these interventions are indicated, they should be considered as a first line of treatment. Further, psychosocial and behavioral interventions almost always should be implemented instead of or in conjunction with medications that are used in the treatment of DBDs. Further, in choosing appropriate treatments for DBDs, the etiology of the DB must be considered. For example, one study found that olanzapine was an effective treatment for impulsive-affective DB but not for controlled-predatory DB (Masi et al., 2006). Although impulsive forms of severely aggressive behavior may respond well to being treated with AAMs, socialized or controlled aggression may not have such a response to pharmacotherapy (Findling, 2003; Masi et al., 2006). Similarly, parent management training is highly effective in treating DB resulting from inconsistent parenting, whereas DB resulting from the dispositions (e.g., psychopathy, callous-unemotional traits) of children and adolescents may be more amenable to treatments that improve

empathy, prosocial behaviors, social skills, and problem-solving skills in addition to parent management training (Frick et al., 2003; Frick, O'Brien, Wootton, & McBurnett, 1994; Kazdin, 1995, 2007). Thus, any researchers examining use of AAMs and other medications in children and adolescents are encouraged to explore their mechanisms of action and the varying etiologies of DB. For example, McKinney and Renk (2007) proposed possible etiological explanations regarding why some DBs respond well to some treatments and poorly to others. Although research in this field is relatively young, researchers and practitioners are beginning to formulate recommendations based on their findings and experiences. Consistent with the discussion above, De Deyn and Buitelaar (2006) recommended that the treatment of chronic disorders should begin with psychosocial interventions. If such interventions prove ineffective alone, medications to treat the primary diagnosis then should be used (e.g., an antidepressant for Depression, a stimulant for Attention-Deficit/Hyperactivity Disorder). Should this approach not ameliorate DB, non-specific medications then may be considered (e.g., the use of AAMs to treat agitation and aggression in the context of a non-Psychotic Disorder) as an adjunct to primary therapy and used only as a last resort. Further, Based on the aforementioned literature, several other recommendations may be derived as well. In particular, AAMs should be used in the treatment of DB only when the following points are true: 1) a reasonable etiology of the DB has been determined, 2) at least three psychosocial/behavioral interventions have been implemented, 3) a reasonable explanation for the lack of effectiveness of the psychosocial/behavioral interventions is provided, 4) the DB is determined to be wholly intransigent, and 5) the DB would cause more potential harm than the worst reasonably expected side effects (e.g., somnolence and weight gain may be preferred over head trauma resulting from self-injurious behavior). Further, if AAMs, and other psychiatric medications for that matter, are prescribed, their effects should be monitored closely (e.g., as recommended by Zito, Derivan, et al., 2008) and strict guidelines in dosing should be followed. For example, higher doses of risperidone (e.g., 6 mg/day) are associated with Movement Disorders and other severe AEs. In contrast, lower doses of risperidone (e.g., 1.5 mg/day) that achieve ameliorative effects are associated with fewer AEs, although some studies report EPS and drooling even at low doses (Findling et al., 2004). Thus, medical professionals must be careful not to overmedicate children and adolescents in an attempt to achieve an optimal therapeutic response (Findling, 2003). Higher than normal doses of medications are unlikely to increase their benefits and are especially likely to increase the risk of AEs (Findling, 2003). Medical professionals should strive to avoid overmedicating children and adolescents by using caution and using the lowest possible dose (Findling, 2003). In monitoring patients in practice or participants in research, using reliable and valid methods of assessing efficacy is encouraged strongly. Many studies described above included ratings, observations, and other outcome assessments to measure efficacy, and although consistency across the studies is observed (i.e., many studies used the ABC, CGI, and/ or N-CBRF), determining a gold standard in efficacy assessment should be a priority. Not only would this assist with practitioners choosing effective assessments, it also would allow for easier comparisons across research studies. At minimum, practitioners and researchers alike should use direct observation, multiple informants, and repeated measurement over time when conducting behavioral–pharmacological research. Finally, Sivaprasad et al. (2006) found that doctors raised several concerns regarding AAMs in the following areas: a) the occurrence of AEs in the short- and long-term, b) a lack of clear monitoring guidelines and difficulties monitoring outpatients, c) possible differences in adult populations, d) the off-label use of medications to treat children against a background of increasing parental concern with such use, e) a lack of research and consensus on the use of medications with children and adolescents, f) a difficulty gaining experience and confidence, and g) the

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pressure of time (e.g., demands for quick cures) and outside agencies (e.g., demands by pharmaceutical companies). These doctors further stated that the use of AAMs is recommended only when absolutely necessary, in the smallest possible dose for the shortest possible duration, and in conjunction with other psychological treatments. Also, these doctors suggested obtaining a second opinion, conducting a riskbenefit analysis, and openly discussing possible issues with parents before making a decision to prescribe these medications to children and adolescents (Sivaprasad et al., 2006). Thus, the bottom line on the use of AAMs with children and adolescents with DB remains the same: “It is widely acknowledged that there are insufficient data about the effects of these agents on various aspects of development such as growth, puberty, and cognition and one needs to proceed with caution until more evidence from systematic research is available” (Sivaprasad et al., 2006, p. 166). References Akdag, S. T., Fettahoglu, E. C., & Ozatalay, E. (2009). Pedal edema induced by low-dose risperidone monotherapy in a child. Journal of Child and Adolescent Psychopharmacology, 19, 481−482. Caldwell, M. F., Malterer, M., Umstead, D., & McCormick, D. J. (2008). A retrospective evaluation of adjunctive risperidone treatment in severely behaviorally disordered boys receiving psychosocial treatment. Journal of Child and Adolescent Psychopharmacology, 18, 34−43. Correll, C. U., & Kane, J. M. (2007). One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: A systematic review. Journal of Child and Adolescent Psychopharmacology, 17, 647−655. Coskun, M., & Mukaddes, N. M. (2008). Possible risperidone-related gastrointestinal bleeding or epistaxis in two pediatric cases. Journal of Child and Adolescent Psychopharmacology, 18, 299−300. Croarkin, P. E., Emslie, G. J., & Mayes, T. L. (2008). Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: A review of published cases. Journal of Clinical Psychiatry, 69, 1157−1165. Croonenberghs, J., Fegert, J. M., Findling, R. L., De Smedt, G., Van Dongen, S., & the Risperidone Disruptive Behavior Study Group. (2005). Risperidone in children with Disruptive Behavior Disorders and subaverage intelligence: A 1-year, open-label study of 504 patients. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 64−72. De Deyn, P. P., & Buitelaar, J. (2006). Risperidone in the management of agitation and aggression associated with psychiatric disorders. European Psychiatry, 21, 21−28. Elbe, D. (2009). Commentary to QTc prolongation associated with atypical antipsychotic use in the treatment of adolescent-onset Anorexia Nervosa. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 18, 64. Eldevik, S., Hastings, R. P., Hughes, J. C., Jahr, E., Eikeseth, S., & Cross, S. (2009). Meta-analysis of early intensive behavioral intervention for children with autism. Journal of Clinical Child and Adolescent Psychology, 38, 439−450. Erdogan, A., Atasoy, N., Akkurt, H., Ozturk, D., Karaahmet, E., Yalug, I., et al. (2008). Risperidone and liver function tests in children and adolescents: A short-term prospective study. Progress in Neuropsychopharmacology and Biological Psychiatry, 32, 849−857. Findling, R. (2003). Dosing of atypical antipsychotics in children and adolescents. Primary Care Companion Journal of Clinical Psychiatry, 5, 10−13. Findling, R. L., Aman, R. G., Eerdekens, M., Derivan, A., & Lyons, B. (2004). Long-term, open-label study of risperidone in children with severe disruptive behaviors and below-average IQ. American Journal of Psychiatry, 161, 677−684. Fraguas, D., Merchan-Naranjo, J., Laita, P., Parallada, M., Moreno, D., Ruiz-Sancho, A., et al. (2008). Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics. Journal of Clinical Psychiatry, 69, 1166−1175. Frick, P. J., Cornell, A. H., Bodin, S. D., Dane, H. E., Barry, C. T., & Loney, B. R. (2003). Callous-unemotional traits and developmental pathways to severe conduct problems. Developmental Psychology, 39, 246−260. Frick, P. J., O'Brien, B. S., Wootton, J. M., & McBurnett, K. (1994). Psychopathy and conduct problems in children. Journal of Abnormal Psychology, 103, 700−707. Greenaway, M., & Elbe, D. (2009). Focus on aripiprazole: A review of its use in child and adolescent psychiatry. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 18, 250−260. Haas, M., Karcher, K., & Pandina, G. J. (2008). Treating Disruptive Behavior Disorders with risperidone: A 1-year, open-label safety study in children and adolescents. Journal of Child and Adolescent Psychopharmacology, 18, 337−346. Halperin, J. M., Kalmar, J. H., Schulz, K. P., Marks, D. J., Sharma, V., & Newcorn, J. H. (2006). Elevated childhood serotonergic function protects against adolescent

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