EDITORIAL
Not Just Another Antipsychotic-for-ConductProblems Trial Joseph C. Blader,
I
f you follow developments in child and adolescent psychiatry, it is understandable if, when you glanced at this issue’s contents, you asked, “Does the world really need another antipsychotic-beats-placebo trial for childhood aggression? Does Seattle really need another Starbucks?” Yet, just as a seemingly superfluous coffee shop can fulfill a need, for instance, by opening on your block, many features of the study by Aman et al.1 that compared risperidone (RISP) with placebo when they were added to methylphenidate in aggressive children with attentiondeficit/hyperactivity disorder (ADHD) make it exceptionally useful indeed. So before appraising this important trial’s significance for clinical practice and research, let us take a moment to consider the innovations through which it transcends its predecessors. First, this trial’s design helps to reconcile an incongruity between practice guidelines and evidence for the treatment of a large patient population. Volatile, impulsive children with brittle frustration tolerance who display persistent aggressive behavior are the dominant preadolescent group receiving mental health care.2 These problems most often emerge on a substrate of weak impulse control, and ADHD is ubiquitous in these youngsters.3 Accordingly, guidelines suggest that initial pharmacotherapy target ADHD using agents well established for that purpose.4,5 This is sensible guidance. Stimulant monotherapy can alleviate many manifestations of ADHD and the conduct problems often associated with it, including chronic aggressive behavior. These medications are generally well tolerated and one’s response to a stimulant regimen can be deduced in a matter of days. The effect sizes of stimulants for the broader spectrum of ADHD symptoms remain unmatched. If, after an adequate stimulant medication trial,
PhD
aggressive behavior persists, adding another compound, such as a second-generation antipsychotic (SGA), may be indicated.4,5 However, the evidence base for antipsychotic treatment of aggression is rooted chiefly in trials that did not use this stepped-care approach. Some trials let patients stay on pre-enrollment stimulant treatment, but this passive approach has drawbacks. There is no way to tell whether the regimen is helpful for ADHD symptoms or aggression, whether it could be improved on, or whether it has in fact worsened irritability and rage. Adherence to such “allowed” stimulant treatment is never mentioned. Therefore, with the few exceptions noted in the articles,6,7 SGAs for aggression in children with ADHD remain essentially untested in their recommended use: as add-on therapy for those demonstrably underresponsive to first-line ADHD therapy. Aman et al. overcome this deficiency in our literature. Second, it is great to see a trial in this area use inclusion criteria that contain a meaningful threshold of aggressiveness. Most often, some surrogate characteristic defines the patient sample (e.g., irritability, rating scales that include a broader range of nonaggressive behavior problems, diagnoses of conduct disorder). Third, affording all families psychosocial therapy has little precedent in SGA trials for aggressive youngsters, but I believe is important to do for numerous methodologic and ethical reasons. Fourth, the effort to distinguish treatment effect on proactive aggression versus reactive aggression furnishes worthwhile data. Now on to what this study teaches us. The trial’s overall finding is that children randomized to have RISP added to methylphenidate, the latter openly titrated during the first 3 weeks, had greater decreases on parent-rated disruptive behaviors than those allocated to receive adjunctive placebo. The magnitude of effect was
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
www.jaacap.org
17
BLADER
moderate (effect size 0.52). At the trial’s end, blinded evaluators judged 79% of the RISPtreated patients as “much” or “very much” improved compared with 70% of those on placebo; the number needed to treat for 1 patient to achieve this outcome attributable to RISP was 11, and the group difference was not statistically significant. Similarly, 72% in the RISP group were rated as no more than “mildly ill” after treatment, whereas 59% in the placebo group were—also not significant and the number needed to treat was approximately 8. Compared with other trials for severe aggressive behavior, this trial showed smaller benefit for RISP over placebo, which the authors discuss at length. Because satisfactory response in placebo-treated groups was uncommon in earlier trials, the effect size reported here is smaller here since so many children got better without antipsychotic exposure. The trajectory of behavioral ratings over time (Figure 2 in Aman et al.1) showed that the initial 3 weeks of stimulant monotherapy for everyone did much of the heavy lifting toward the ultimate response measured at week 9. In the placebo group, continuation on the stimulant and behavioral therapy regimen culminated in even further decreases in conduct problem ratings. In the context of these results, the authors discuss whether stimulant-plus-RISP “co-therapy is worth the added expense, inconvenience, and potential risks that may accompany use of more than one drug.” The enduring, widespread public and practitioner concerns about polytherapy’s proliferation in children with severe behavioral disorders, SGA use in particular, and the minuscule evidence base for its value make the question an almost existential one for child and adolescent psychiatry and you should read their consideration of it. However, suppose we tweak the topic to ask more specifically, “Should clinicians adopt this trial’s strategy of a 3-week stimulant monotherapy period and then start RISP if there is ‘room for improvement’?” The ensuing discussion would show the depth of the gratitude we owe these investigators, because they contribute, at long last, real data to formulate detailed treatment guidelines affecting the care of many thousands of children.8-10 Indeed, these results seem to show that a longer period of well-monitored stimulant monotherapy accompanied by competent psychosocial treatment is a wiser course than starting adjunctive SGA therapy. Judging from the symptom trajectories in Figure 2, unless we find strong predictors
at 21 days that show whose progress is likely to stall, or unless dangerous behavior distills the choices to start another drug or get hospitalized, introducing another compound much before, say, 5 to 6 weeks seems hasty. Moreover, it is doubtful that 21 days is a suitable maximum period to establish an optimal stimulant regimen. Greater flexibility in dosing, agent selection, and overall duration might have culminated in an even greater clinical response during the monotherapy phase. As a veteran of trials involving stimulant-optimization and behavior therapy before randomization to adjunctive treatments for those whose aggression persists,11-13 I know how difficult they are. I understand the choices Aman et al. made to bracket the open monotherapy phase to a manageable, relatively brief, and uniform period. However, the exigencies of an efficient clinical trial do not always match what does, or should, happen in clinical care. My colleagues and I opted for a variable-length stimulant monotherapy lead-in whose titration algorithm includes more dose options and assessment occasions to reconfirm response. Our total time from baseline to the final assessment that determines eligibility for the adjunctive treatment phase of the trials is typically 5 to 7 weeks, often longer, which also allows more time for the behavioral interventions to gain traction. In this context, we have consistently found that at least half the patients show remission of their aggressive behavior during this lead-in phase. In comparison, Aman et al. reported that only 8 of their 138 patients responded well enough in the 3-week monotherapy period to preclude adding the other compound (RISP or placebo). I also suspect that more time devoted to optimizing first-line treatment picks the low-hanging fruit more thoroughly so that placebo response rates decrease, improving statistical power. For instance, the incidence of remitted aggression in children randomized to add placebo to optimized stimulant in our first trial was only 15% versus 57% of those randomized to add divalproex sodium. Aman et al., as noted, reported response rates in the add-on placebo condition of approximately 60% to 70%. Another way to assess whether first-line ADHD treatment has really been titrated to optimal effect is to see how much ADHD improves. Curiously, Aman et al. do not discuss their ADHD symptom outcomes over the trial’s course, but I hope they do in their subsequent reports.
JOURNAL 18
www.jaacap.org
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
EDITORIAL
After all, ADHD is a major source of these children’s problems and conflicts. One sees in Table 2 a nice decrease in the first 3 weeks, from higher than the 97th percentile at baseline to the 80th to 85th percentile range, and more improvement was in store for those who continued to adjunctive placebo, down to the 70th to 75th percentile range. Although advantageous, it is hard to know whether this is as good as it gets—although we try to treat to remission for ADHD, these are more impaired children. In any event, adjunctive RISP did not significantly affect ADHD symptoms. Combined with the results of Findling et al.,14 it seems that RISP offers little bang for the buck for the ADHD symptoms that are a great burden for these youngsters. This result supports another reason, in addition to adverse effect risks, for starting stimulant treatment first rather than an SGA first, at least in those without major developmental disorders. Another outcome begging for more discussion is aggressive behavior. Although they used a cutoff on the Overt Aggression Scale–Modified to identify a meaningful threshold of aggression severity to enroll in this trial, one wonders why Overt Aggression Scale–Modified scores were not presented as an outcome. Did treatment affect the likelihood that one is now below this threshold? This study’s measurement of proactive and reactive aggression led the authors to conclude that “Augmented reduced reactive (‘hot’) aggression more than did Basic treatment, whereas treatment effects on proactive (‘cold’) aggression were not significantly different.” This entirely accurate statement does not, however, mean that behaviors measured by the proactive scale were
resistant to change: from baseline to trial end, mean proactive aggression ratings decreased for this cohort (unadjusted effect size estimate was 1.26), just not preferentially in those receiving adjunctive RISP. The study’s first author has for decades been a true pioneer in psychopharmacologic research that has led to helping many youth. This was not always a comfortable niche to occupy, because much of the work was undertaken during an era of ideological opposition, much fiercer than it is now, to medication as a means to alleviate severely disturbed behavior and cognition in young people. Today’s more balanced, pragmatic approach, whatever its shortcomings, would not be here but for these efforts. Because it heralds the continued maturation of our field, it is only fitting that a group under his leadership makes the important contribution this issue contains and we should congratulate them all heartily for it. &
Accepted October 24, 2013. Dr. Blader is with the University of Texas Health Science Center at San Antonio. Disclosure: Dr. Blader has received research grant support from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression (now the Brain and Behavior Research Foundation), Abbott Laboratories, and Supernus Pharmaceuticals; has served as a consultant to Shire and Supernus Pharmaceuticals; and has received research and service funding from the Texas State Health and Human Services Commission. Correspondence to Joseph C. Blader, PhD, Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Room 742F, San Antonio, TX 78229; e-mail: [email protected] 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2013.10.007
REFERENCES 1. Aman MG, Bukstein OG, Gadow KD et al. What does risperidone add to stimulant and parent training for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014;53:47-60. 2. US Public Health Service. Report of the Surgeon General’s Conference on Children’s Mental Health: A National Action Agenda. Washington, DC: US Department of Health and Human Services; 2000. 3. Blader JC, Jensen PS. Aggression in children: an integrative approach. In: Martin A, Volkmar FR, eds. Lewis’ Child and Adolescent Psychiatry: A Comprehensive Textbook. 4th ed. Baltimore: Lippincott, Williams, and Wilkins; 2007:467-483. 4. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry. 2006;45:642-657. 5. Pappadopulos E, Macintyre JC II, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry. 2003;42:145-161.
6. Armenteros JL, Lewis JE, Davolos M. Risperidone augmentation for treatment-resistant aggression in attention-deficit/ hyperactivity disorder: a placebo-controlled pilot study. J Am Acad Child Adolesc Psychiatry. 2007;46:558-565. 7. Kronenberger WG, Giauque AL, Lafata DE, Bohnstedt BN, Maxey LE, Dunn DW. Quetiapine addition in methylphenidate treatment-resistant adolescents with comorbid ADHD, conduct/ oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol. 2007;17: 334-347. 8. Comer JS, Olfson M, Mojtabai R. National trends in child and adolescent psychotropic polypharmacy in office-based practice, 1996-2007. J Am Acad Child Adolesc Psychiatry. 2010;49:1001-1010. 9. Martin A, Van Hoof T, Stubbe D, Sherwin T, Scahill L. Multiple psychotropic pharmacotherapy among child and adolescent enrollees in Connecticut Medicaid managed care. Psychiatr Serv. 2003;54:72-77. 10. Duffy FF, Narrow WE, Rae DS, et al. Concomitant pharmacotherapy among youths treated in routine psychiatric practice. J Child Adolesc Psychopharmacol. 2005;15:12-25.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
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BLADER
11. Blader JC, Schooler NR, Jensen PS, Pliszka SR, Kafantaris V. Adjunctive divalproex sodium vs. placebo for children with ADHD and aggression refractory to stimulant monotherapy. Am J Psychiatry. 2009;166:1392-1401. 12. Blader JC, Pliszka SR, Jensen PS, Schooler NR, Kafantaris V. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics. 2010;126: e796-e806.
13. Blader JC, Pliszka SR, Kafantaris V et al. Callous-Unemotional Traits, Proactive Aggression, and Treatment Outcomes of Aggressive Children With Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2013;52:1281-1293. 14. Findling RL, McNamara NK, Branicky LA, Schluchter MD, Lemon E, Blumer JL. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry. 2000;39:509-516.
JOURNAL 20
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OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
Not Just Another Antipsychotic-for-ConductProblems Trial Joseph C. Blader,
I
f you follow developments in child and adolescent psychiatry, it is understandable if, when you glanced at this issue’s contents, you asked, “Does the world really need another antipsychotic-beats-placebo trial for childhood aggression? Does Seattle really need another Starbucks?” Yet, just as a seemingly superfluous coffee shop can fulfill a need, for instance, by opening on your block, many features of the study by Aman et al.1 that compared risperidone (RISP) with placebo when they were added to methylphenidate in aggressive children with attentiondeficit/hyperactivity disorder (ADHD) make it exceptionally useful indeed. So before appraising this important trial’s significance for clinical practice and research, let us take a moment to consider the innovations through which it transcends its predecessors. First, this trial’s design helps to reconcile an incongruity between practice guidelines and evidence for the treatment of a large patient population. Volatile, impulsive children with brittle frustration tolerance who display persistent aggressive behavior are the dominant preadolescent group receiving mental health care.2 These problems most often emerge on a substrate of weak impulse control, and ADHD is ubiquitous in these youngsters.3 Accordingly, guidelines suggest that initial pharmacotherapy target ADHD using agents well established for that purpose.4,5 This is sensible guidance. Stimulant monotherapy can alleviate many manifestations of ADHD and the conduct problems often associated with it, including chronic aggressive behavior. These medications are generally well tolerated and one’s response to a stimulant regimen can be deduced in a matter of days. The effect sizes of stimulants for the broader spectrum of ADHD symptoms remain unmatched. If, after an adequate stimulant medication trial,
PhD
aggressive behavior persists, adding another compound, such as a second-generation antipsychotic (SGA), may be indicated.4,5 However, the evidence base for antipsychotic treatment of aggression is rooted chiefly in trials that did not use this stepped-care approach. Some trials let patients stay on pre-enrollment stimulant treatment, but this passive approach has drawbacks. There is no way to tell whether the regimen is helpful for ADHD symptoms or aggression, whether it could be improved on, or whether it has in fact worsened irritability and rage. Adherence to such “allowed” stimulant treatment is never mentioned. Therefore, with the few exceptions noted in the articles,6,7 SGAs for aggression in children with ADHD remain essentially untested in their recommended use: as add-on therapy for those demonstrably underresponsive to first-line ADHD therapy. Aman et al. overcome this deficiency in our literature. Second, it is great to see a trial in this area use inclusion criteria that contain a meaningful threshold of aggressiveness. Most often, some surrogate characteristic defines the patient sample (e.g., irritability, rating scales that include a broader range of nonaggressive behavior problems, diagnoses of conduct disorder). Third, affording all families psychosocial therapy has little precedent in SGA trials for aggressive youngsters, but I believe is important to do for numerous methodologic and ethical reasons. Fourth, the effort to distinguish treatment effect on proactive aggression versus reactive aggression furnishes worthwhile data. Now on to what this study teaches us. The trial’s overall finding is that children randomized to have RISP added to methylphenidate, the latter openly titrated during the first 3 weeks, had greater decreases on parent-rated disruptive behaviors than those allocated to receive adjunctive placebo. The magnitude of effect was
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
www.jaacap.org
17
BLADER
moderate (effect size 0.52). At the trial’s end, blinded evaluators judged 79% of the RISPtreated patients as “much” or “very much” improved compared with 70% of those on placebo; the number needed to treat for 1 patient to achieve this outcome attributable to RISP was 11, and the group difference was not statistically significant. Similarly, 72% in the RISP group were rated as no more than “mildly ill” after treatment, whereas 59% in the placebo group were—also not significant and the number needed to treat was approximately 8. Compared with other trials for severe aggressive behavior, this trial showed smaller benefit for RISP over placebo, which the authors discuss at length. Because satisfactory response in placebo-treated groups was uncommon in earlier trials, the effect size reported here is smaller here since so many children got better without antipsychotic exposure. The trajectory of behavioral ratings over time (Figure 2 in Aman et al.1) showed that the initial 3 weeks of stimulant monotherapy for everyone did much of the heavy lifting toward the ultimate response measured at week 9. In the placebo group, continuation on the stimulant and behavioral therapy regimen culminated in even further decreases in conduct problem ratings. In the context of these results, the authors discuss whether stimulant-plus-RISP “co-therapy is worth the added expense, inconvenience, and potential risks that may accompany use of more than one drug.” The enduring, widespread public and practitioner concerns about polytherapy’s proliferation in children with severe behavioral disorders, SGA use in particular, and the minuscule evidence base for its value make the question an almost existential one for child and adolescent psychiatry and you should read their consideration of it. However, suppose we tweak the topic to ask more specifically, “Should clinicians adopt this trial’s strategy of a 3-week stimulant monotherapy period and then start RISP if there is ‘room for improvement’?” The ensuing discussion would show the depth of the gratitude we owe these investigators, because they contribute, at long last, real data to formulate detailed treatment guidelines affecting the care of many thousands of children.8-10 Indeed, these results seem to show that a longer period of well-monitored stimulant monotherapy accompanied by competent psychosocial treatment is a wiser course than starting adjunctive SGA therapy. Judging from the symptom trajectories in Figure 2, unless we find strong predictors
at 21 days that show whose progress is likely to stall, or unless dangerous behavior distills the choices to start another drug or get hospitalized, introducing another compound much before, say, 5 to 6 weeks seems hasty. Moreover, it is doubtful that 21 days is a suitable maximum period to establish an optimal stimulant regimen. Greater flexibility in dosing, agent selection, and overall duration might have culminated in an even greater clinical response during the monotherapy phase. As a veteran of trials involving stimulant-optimization and behavior therapy before randomization to adjunctive treatments for those whose aggression persists,11-13 I know how difficult they are. I understand the choices Aman et al. made to bracket the open monotherapy phase to a manageable, relatively brief, and uniform period. However, the exigencies of an efficient clinical trial do not always match what does, or should, happen in clinical care. My colleagues and I opted for a variable-length stimulant monotherapy lead-in whose titration algorithm includes more dose options and assessment occasions to reconfirm response. Our total time from baseline to the final assessment that determines eligibility for the adjunctive treatment phase of the trials is typically 5 to 7 weeks, often longer, which also allows more time for the behavioral interventions to gain traction. In this context, we have consistently found that at least half the patients show remission of their aggressive behavior during this lead-in phase. In comparison, Aman et al. reported that only 8 of their 138 patients responded well enough in the 3-week monotherapy period to preclude adding the other compound (RISP or placebo). I also suspect that more time devoted to optimizing first-line treatment picks the low-hanging fruit more thoroughly so that placebo response rates decrease, improving statistical power. For instance, the incidence of remitted aggression in children randomized to add placebo to optimized stimulant in our first trial was only 15% versus 57% of those randomized to add divalproex sodium. Aman et al., as noted, reported response rates in the add-on placebo condition of approximately 60% to 70%. Another way to assess whether first-line ADHD treatment has really been titrated to optimal effect is to see how much ADHD improves. Curiously, Aman et al. do not discuss their ADHD symptom outcomes over the trial’s course, but I hope they do in their subsequent reports.
JOURNAL 18
www.jaacap.org
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
EDITORIAL
After all, ADHD is a major source of these children’s problems and conflicts. One sees in Table 2 a nice decrease in the first 3 weeks, from higher than the 97th percentile at baseline to the 80th to 85th percentile range, and more improvement was in store for those who continued to adjunctive placebo, down to the 70th to 75th percentile range. Although advantageous, it is hard to know whether this is as good as it gets—although we try to treat to remission for ADHD, these are more impaired children. In any event, adjunctive RISP did not significantly affect ADHD symptoms. Combined with the results of Findling et al.,14 it seems that RISP offers little bang for the buck for the ADHD symptoms that are a great burden for these youngsters. This result supports another reason, in addition to adverse effect risks, for starting stimulant treatment first rather than an SGA first, at least in those without major developmental disorders. Another outcome begging for more discussion is aggressive behavior. Although they used a cutoff on the Overt Aggression Scale–Modified to identify a meaningful threshold of aggression severity to enroll in this trial, one wonders why Overt Aggression Scale–Modified scores were not presented as an outcome. Did treatment affect the likelihood that one is now below this threshold? This study’s measurement of proactive and reactive aggression led the authors to conclude that “Augmented reduced reactive (‘hot’) aggression more than did Basic treatment, whereas treatment effects on proactive (‘cold’) aggression were not significantly different.” This entirely accurate statement does not, however, mean that behaviors measured by the proactive scale were
resistant to change: from baseline to trial end, mean proactive aggression ratings decreased for this cohort (unadjusted effect size estimate was 1.26), just not preferentially in those receiving adjunctive RISP. The study’s first author has for decades been a true pioneer in psychopharmacologic research that has led to helping many youth. This was not always a comfortable niche to occupy, because much of the work was undertaken during an era of ideological opposition, much fiercer than it is now, to medication as a means to alleviate severely disturbed behavior and cognition in young people. Today’s more balanced, pragmatic approach, whatever its shortcomings, would not be here but for these efforts. Because it heralds the continued maturation of our field, it is only fitting that a group under his leadership makes the important contribution this issue contains and we should congratulate them all heartily for it. &
Accepted October 24, 2013. Dr. Blader is with the University of Texas Health Science Center at San Antonio. Disclosure: Dr. Blader has received research grant support from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression (now the Brain and Behavior Research Foundation), Abbott Laboratories, and Supernus Pharmaceuticals; has served as a consultant to Shire and Supernus Pharmaceuticals; and has received research and service funding from the Texas State Health and Human Services Commission. Correspondence to Joseph C. Blader, PhD, Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Room 742F, San Antonio, TX 78229; e-mail: [email protected] 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2013.10.007
REFERENCES 1. Aman MG, Bukstein OG, Gadow KD et al. What does risperidone add to stimulant and parent training for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014;53:47-60. 2. US Public Health Service. Report of the Surgeon General’s Conference on Children’s Mental Health: A National Action Agenda. Washington, DC: US Department of Health and Human Services; 2000. 3. Blader JC, Jensen PS. Aggression in children: an integrative approach. In: Martin A, Volkmar FR, eds. Lewis’ Child and Adolescent Psychiatry: A Comprehensive Textbook. 4th ed. Baltimore: Lippincott, Williams, and Wilkins; 2007:467-483. 4. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry. 2006;45:642-657. 5. Pappadopulos E, Macintyre JC II, Crismon ML, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry. 2003;42:145-161.
6. Armenteros JL, Lewis JE, Davolos M. Risperidone augmentation for treatment-resistant aggression in attention-deficit/ hyperactivity disorder: a placebo-controlled pilot study. J Am Acad Child Adolesc Psychiatry. 2007;46:558-565. 7. Kronenberger WG, Giauque AL, Lafata DE, Bohnstedt BN, Maxey LE, Dunn DW. Quetiapine addition in methylphenidate treatment-resistant adolescents with comorbid ADHD, conduct/ oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol. 2007;17: 334-347. 8. Comer JS, Olfson M, Mojtabai R. National trends in child and adolescent psychotropic polypharmacy in office-based practice, 1996-2007. J Am Acad Child Adolesc Psychiatry. 2010;49:1001-1010. 9. Martin A, Van Hoof T, Stubbe D, Sherwin T, Scahill L. Multiple psychotropic pharmacotherapy among child and adolescent enrollees in Connecticut Medicaid managed care. Psychiatr Serv. 2003;54:72-77. 10. Duffy FF, Narrow WE, Rae DS, et al. Concomitant pharmacotherapy among youths treated in routine psychiatric practice. J Child Adolesc Psychopharmacol. 2005;15:12-25.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
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BLADER
11. Blader JC, Schooler NR, Jensen PS, Pliszka SR, Kafantaris V. Adjunctive divalproex sodium vs. placebo for children with ADHD and aggression refractory to stimulant monotherapy. Am J Psychiatry. 2009;166:1392-1401. 12. Blader JC, Pliszka SR, Jensen PS, Schooler NR, Kafantaris V. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics. 2010;126: e796-e806.
13. Blader JC, Pliszka SR, Kafantaris V et al. Callous-Unemotional Traits, Proactive Aggression, and Treatment Outcomes of Aggressive Children With Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2013;52:1281-1293. 14. Findling RL, McNamara NK, Branicky LA, Schluchter MD, Lemon E, Blumer JL. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry. 2000;39:509-516.
JOURNAL 20
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OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 1 JANUARY 2014
