EDITORIAL
Can Children With Callous and Unemotional Traits Be Treated Successfully? Jeffrey H. Newcorn,
B
y now many readers will recognize the term callous and unemotional (CU) as a “clinical specifier” that was added to DSM-5 to describe a subgroup of youth with conduct disorder (CD). DSM-5 lists 4 behavioral indicators (i.e., lack of remorse or guilt, callous/ lack of empathy, lack of concern about performance, and shallow or deficient affect) and requires that 2 be present. However, although the DSM definition of CU traits may be familiar, the rationale for adding the CU clinical specifier and the clinical import of identifying youth with these features may be less clear. To briefly review, a wealth of literature has indicated that CU traits constitute one of several key dimensions identified in adults with psychopathy, and a substantial body of research has examined the potential utility of this construct for understanding conduct problems in children and adolescents. Findings across multiple studies have indicated that among antisocial youth, those with CU traits present with a relatively stable and severe pattern of aggressive behavior and are at increased risk for early-onset delinquency and later antisocial and delinquent behavior (for review, see Frick et al.1). Moreover, subtyping CD behaviors according to the presence of CU traits has been shown to be relevant for girls and boys.2 The heritability of CU traits is noted to be quite high and there appear to be characteristic underlying neurobiological findings—specifically, lower indices of autonomic function such as heart rate variability,3 decreased activation of the amygdala during functional magnetic resonance imaging when viewing pictures of fearful faces,4 and decreased connectivity between the amygdala and orbitofrontal cortex in relation to moral decision making.5 As a rule, youth with CU traits are characterized by lack of concern or empathy for others (but different from the lack of empathy that is typically seen in autistic spectrum
M.D.
disorders), excessive and often inappropriate pursuit of reward, and poor processing of punishment cues. Moreover, they often present with a combination of instrumental or proactive aggression (i.e., for gain) and reactive (i.e., impulsive) aggression. Youth with CU traits have historically been described as resistant to treatment, and findings from several recent psychosocial treatment studies support this contention. However, recent studies have suggested that targeted psychosocial interventions1 or the combination of stimulant medication and behavior therapy6 may be useful. In this issue of the Journal, Blader et al.7 conducted an open stimulant optimization protocol as part of a larger study of youth with attentiondeficit/hyperactivity disorder (ADHD) and aggression. One hundred sixty children 6 to 13 years old with ADHD, oppositional defiant disorder, or CD and aggression participated in the protocol. The group was well assessed with regard to ADHD, aggression, aggression subtypes, and CU traits using state-of-the-art measurements. Because this was primarily a preadolescent population, assessments of these constructs were provided by parents. Twenty-six of the children (16% of the sample) would have met criteria for the DSM CU trait specifier, with the caveat that the large majority of participants had oppositional defiant disorder and not CD. Children were partial responders to d,lmethylphenidate or its equivalent. After washout of existing medication, children were titrated with different stimulant formulations; most received a triphasic osmotically releasing methylphenidate. Principles that guided stimulant optimization were: cover the entire day, if possible; use a high enough dose; and use multiple stimulant classes and formulations before deciding whether there was a good enough response. The stimulant titration followed an “open” design—neither the
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
www.jaacap.org
1257
NEWCORN
parents nor the treatment team were blinded. The children also received a family-based behavioral treatment that is known to be effective for ADHD and aggression. The main study findings are that pretreatment ratings of CU traits and proactive aggression did not negatively predict remission of aggression; children whose aggression remitted had a decrease in CU traits (small effect) and proactive aggression (larger; approaching moderate effect). The percentage of remitters in the CU group was somewhat lower than in the non-CU group, although the numbers are very small and the results were certainly not significant. Proactive aggression was associated with greater severity of aggression and therefore a trend toward greater improvement with treatment. This article presents secondary analyses that examined potential moderating effects of pretreatment CU traits and proactive aggression on stimulant treatment of aggression. The investigators provide an excellent review of aggression subtypes and their relation to impulsivity and CU traits and a thoughtful discussion of the study results. The main issue they struggle with is the seemingly counterintuitive finding that children with ADHD and CU traits did not fare worse with stimulant treatment than those without— because most existing data suggest that youth with CU traits respond less well to treatment than those without, and because if stimulants exert their main effects by treating impulsive aggression, youth with proactive aggression would seem less likely to respond. The following characteristics of the study participants and design could have contributed to the findings. First, the subjects were children and not adolescents; the finding of treatment resistance in youth with CU traits is more characteristic of adolescents, in whom CU traits can be more directly assessed. Second, the ratings of CU traits were made by parents, and parents of aggressive children with ADHD might incorrectly describe their children as lacking empathy, guilt, and concerns regarding performance based on their ADHD and impulsive/aggressive symptoms. Third, the DSM specifier of CU traits is intended to describe youth with CD, and most subjects in this study had oppositional-defiant disorder. In fact, only 26 (16%) of these children would have met criteria for CU traits (ignoring the requirement that they would need to have CD). So, this was not a study of the new DSM criterion. Fourth, most children with proactive 1258
www.jaacap.org
aggression in this sample also had reactive aggression (as in other samples), and the improvement they achieved might have been based on response of reactive symptoms. One wonders whether the few children in this study who had proactive and not reactive aggression might have had a lower response to treatment. Fifth, the stimulant trial followed an open design, and families also received a parent-based behavioral treatment. Although these were appropriate decisions for the main study questions, they were less desirable design decisions for the analyses reported here. In an open study, with all subjects receiving active mediation and psychosocial treatment, it is impossible to sort out which intervention accounts for the observed response. The lack of moderator effects for proactive aggression and CU traits might have been partly attributable to a positive response to behavior therapy and not the stimulant medication in youth with CU traits. Whether there are differential effects to medication and psychosocial treatments in youth with CU traits remains an important question for future research. It is also worth considering whether stimulant treatment could have positive effects on proactive aggression in youth with CU traits, independent of the effects on impulsivity and other ADHD symptoms, which could potentially explain why the presence of CU traits did not moderate treatment response. There are published data that potentially support this line. Antisocial behavior in children with CD (two thirds of whom also had ADHD) was improved by methylphenidate treatment, controlling for effects on ADHD symptoms8; pictures of fearful faces during functional magnetic resonance imaging elicited decreased activation of the amygdala,4 and decreased connectivity between the amygdala and orbitofrontal cortex has been observed in relation to impairment in moral decision making5; and amphetamine challenge increased amygdala activation during processing of fearful and angry faces in healthy adults.9 The latter finding was considered to reflect the neural basis underlying the anxiogenic effects of stimulants, but it is interesting to speculate whether this finding offers a rationale for using stimulants to treat a subgroup of individuals characterized by lack of empathy, too little anxiety in situations in which anxiety is appropriate (e.g., individuals with CU traits), and corresponding proactive aggression. Certainly, the data cited here do not provide a solid enough justification for such an
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
EDITORIAL
approach. However, delineating the neurobiological distinctiveness of youth with and without CU traits and using biomarker-informed strategies to predict treatment response in this population could be an important and potentially fruitful area for future research. There are several clinical take-home points to emphasize. First, proactive aggression rarely occurs alone in clinically referred preadolescent youth; rather, it almost always is accompanied by reactive aggression. When proactive aggression is present, it generally signals increased severity of aggression. Second, stimulant treatment is likely to produce improvement in ADHD and aggression, and an optimized approach to titration using multiple stimulant classes and doses greatly improves the likelihood of response. Third, children with proactive aggression and CU traits can be treated successfully in many cases. The investigators indicate that “optimized stimulant therapy warrants strong consideration as firstline intervention for children who present with significant aggression whether or not informants perceive that such behaviors are often volitional.” However, the extent to which improvement was due to medication versus behavior therapy cannot be determined from this study. It is likely that concomitant use of parent-based behavior therapy will add to the degree of improvement observed with stimulants. Moreover, behavioral therapy alone might produce improvement. That was not tested in this study. There will likely be different opinions as to whether it is good or bad news that CU traits did
not moderate response to stimulant treatment in preadolescent youth with ADHD and aggression. The good news is that a group previously thought to be treatment resistant can in fact be treated with some degree of success. The bad news is that the presence of CU traits in this population did not add much over severity in predicting treatment response, and the failure of CU traits to predict differential treatment response could be seen as decreasing the clinical utility of this construct. Nevertheless, the wealth of data supporting the clinical and neurobiological distinctiveness of individuals with CU traits is compelling—although, as this study points out, operationalizing the constructs and fully understanding their meaning is challenging, particularly in children. It is hoped that development of external validators of clinical diagnosis and biomarker-driven treatment approaches will help resolve some of the issues raised by this interesting and very well-done article. & Accepted September 26, 2013. Dr. Newcorn is with Icahn School of Medicine at Mount Sinai. Disclosure: Dr. Newcorn has received research support from Eli Lilly and Co., Ortho-McNeil-Janssen, and Shire. He has served as an advisor and/or consultant to Alcobra, BioBehavioral Diagnostics, Enzymotec, GencoSciences, Neos Therapeutics, Otsuka, Shionogi, Sunovion, and Shire. Correspondence to Jeffrey H. Newcorn, M.D., One Gustave L. Levy Place, Box 1230, New York, NY 10029; e-mail: jeffrey.newcorn@ mssm.edu 0890-8567/$36.00/ª2013 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2013.09.010
REFERENCES 1. Frick PJ, Ray JV, Thornton LC, Kahn RE. Can callous-unemotional traits enhance the understanding, diagnosis, and treatment of serious conduct problems in children and adolescents? A comprehensive review. Psychol Bull. 2013. 2. Pardini D, Stepp S, Hipwell A, Stouthamer-Loeber M, Loeber R. The clinical utility of the proposed DSM-5 callous-unemotional subtype of conduct disorder in young girls. J Am Acad Child Adolesc Psychiatry. 2012;51:62-73. 3. de Wied M, van Boxtel A, Matthys W, Meeus WJ. Verbal, facial and autonomic responses to empathy-eliciting film clips by disruptive male adolescents with high versus low callous-unemotional traits. Abnorm Child Psychol. 2012;40:211-223. 4. Marsh AA, Finger EC, Mitchell DG, et al. Reduced amygdala response to fearful expressions in children and adolescents with callous-unemotional traits and disruptive behavior disorders. Am J Psychiatry. 2008;165:712-720. 5. Marsh AA, Finger EC, Fowler KA, et al. Reduced amygdalaorbitofrontal connectivity during moral judgments in youths with
6.
7.
8.
9.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
disruptive behavior disorders and psychopathic traits. Psychiatry Res. 2011;194:279-286. Waschbusch DA, Carrey NJ, Willoughby MT, King S, Andrade BF. Effects of methylphenidate and behavior modification on the social and academic behavior of children with disruptive behavior disorders: the moderating role of callous/unemotional traits. J Clin Child Adolesc Psychol. 2007;36:629-644. 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. Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollack S. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry. 1997;54:1073-1080. Hariri AR, Mattay VS, Tessitore A, Fera F, Smith WG, Weinberger DR. Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology. 2002;27:1036-1040.
www.jaacap.org
1259
Can Children With Callous and Unemotional Traits Be Treated Successfully? Jeffrey H. Newcorn,
B
y now many readers will recognize the term callous and unemotional (CU) as a “clinical specifier” that was added to DSM-5 to describe a subgroup of youth with conduct disorder (CD). DSM-5 lists 4 behavioral indicators (i.e., lack of remorse or guilt, callous/ lack of empathy, lack of concern about performance, and shallow or deficient affect) and requires that 2 be present. However, although the DSM definition of CU traits may be familiar, the rationale for adding the CU clinical specifier and the clinical import of identifying youth with these features may be less clear. To briefly review, a wealth of literature has indicated that CU traits constitute one of several key dimensions identified in adults with psychopathy, and a substantial body of research has examined the potential utility of this construct for understanding conduct problems in children and adolescents. Findings across multiple studies have indicated that among antisocial youth, those with CU traits present with a relatively stable and severe pattern of aggressive behavior and are at increased risk for early-onset delinquency and later antisocial and delinquent behavior (for review, see Frick et al.1). Moreover, subtyping CD behaviors according to the presence of CU traits has been shown to be relevant for girls and boys.2 The heritability of CU traits is noted to be quite high and there appear to be characteristic underlying neurobiological findings—specifically, lower indices of autonomic function such as heart rate variability,3 decreased activation of the amygdala during functional magnetic resonance imaging when viewing pictures of fearful faces,4 and decreased connectivity between the amygdala and orbitofrontal cortex in relation to moral decision making.5 As a rule, youth with CU traits are characterized by lack of concern or empathy for others (but different from the lack of empathy that is typically seen in autistic spectrum
M.D.
disorders), excessive and often inappropriate pursuit of reward, and poor processing of punishment cues. Moreover, they often present with a combination of instrumental or proactive aggression (i.e., for gain) and reactive (i.e., impulsive) aggression. Youth with CU traits have historically been described as resistant to treatment, and findings from several recent psychosocial treatment studies support this contention. However, recent studies have suggested that targeted psychosocial interventions1 or the combination of stimulant medication and behavior therapy6 may be useful. In this issue of the Journal, Blader et al.7 conducted an open stimulant optimization protocol as part of a larger study of youth with attentiondeficit/hyperactivity disorder (ADHD) and aggression. One hundred sixty children 6 to 13 years old with ADHD, oppositional defiant disorder, or CD and aggression participated in the protocol. The group was well assessed with regard to ADHD, aggression, aggression subtypes, and CU traits using state-of-the-art measurements. Because this was primarily a preadolescent population, assessments of these constructs were provided by parents. Twenty-six of the children (16% of the sample) would have met criteria for the DSM CU trait specifier, with the caveat that the large majority of participants had oppositional defiant disorder and not CD. Children were partial responders to d,lmethylphenidate or its equivalent. After washout of existing medication, children were titrated with different stimulant formulations; most received a triphasic osmotically releasing methylphenidate. Principles that guided stimulant optimization were: cover the entire day, if possible; use a high enough dose; and use multiple stimulant classes and formulations before deciding whether there was a good enough response. The stimulant titration followed an “open” design—neither the
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
www.jaacap.org
1257
NEWCORN
parents nor the treatment team were blinded. The children also received a family-based behavioral treatment that is known to be effective for ADHD and aggression. The main study findings are that pretreatment ratings of CU traits and proactive aggression did not negatively predict remission of aggression; children whose aggression remitted had a decrease in CU traits (small effect) and proactive aggression (larger; approaching moderate effect). The percentage of remitters in the CU group was somewhat lower than in the non-CU group, although the numbers are very small and the results were certainly not significant. Proactive aggression was associated with greater severity of aggression and therefore a trend toward greater improvement with treatment. This article presents secondary analyses that examined potential moderating effects of pretreatment CU traits and proactive aggression on stimulant treatment of aggression. The investigators provide an excellent review of aggression subtypes and their relation to impulsivity and CU traits and a thoughtful discussion of the study results. The main issue they struggle with is the seemingly counterintuitive finding that children with ADHD and CU traits did not fare worse with stimulant treatment than those without— because most existing data suggest that youth with CU traits respond less well to treatment than those without, and because if stimulants exert their main effects by treating impulsive aggression, youth with proactive aggression would seem less likely to respond. The following characteristics of the study participants and design could have contributed to the findings. First, the subjects were children and not adolescents; the finding of treatment resistance in youth with CU traits is more characteristic of adolescents, in whom CU traits can be more directly assessed. Second, the ratings of CU traits were made by parents, and parents of aggressive children with ADHD might incorrectly describe their children as lacking empathy, guilt, and concerns regarding performance based on their ADHD and impulsive/aggressive symptoms. Third, the DSM specifier of CU traits is intended to describe youth with CD, and most subjects in this study had oppositional-defiant disorder. In fact, only 26 (16%) of these children would have met criteria for CU traits (ignoring the requirement that they would need to have CD). So, this was not a study of the new DSM criterion. Fourth, most children with proactive 1258
www.jaacap.org
aggression in this sample also had reactive aggression (as in other samples), and the improvement they achieved might have been based on response of reactive symptoms. One wonders whether the few children in this study who had proactive and not reactive aggression might have had a lower response to treatment. Fifth, the stimulant trial followed an open design, and families also received a parent-based behavioral treatment. Although these were appropriate decisions for the main study questions, they were less desirable design decisions for the analyses reported here. In an open study, with all subjects receiving active mediation and psychosocial treatment, it is impossible to sort out which intervention accounts for the observed response. The lack of moderator effects for proactive aggression and CU traits might have been partly attributable to a positive response to behavior therapy and not the stimulant medication in youth with CU traits. Whether there are differential effects to medication and psychosocial treatments in youth with CU traits remains an important question for future research. It is also worth considering whether stimulant treatment could have positive effects on proactive aggression in youth with CU traits, independent of the effects on impulsivity and other ADHD symptoms, which could potentially explain why the presence of CU traits did not moderate treatment response. There are published data that potentially support this line. Antisocial behavior in children with CD (two thirds of whom also had ADHD) was improved by methylphenidate treatment, controlling for effects on ADHD symptoms8; pictures of fearful faces during functional magnetic resonance imaging elicited decreased activation of the amygdala,4 and decreased connectivity between the amygdala and orbitofrontal cortex has been observed in relation to impairment in moral decision making5; and amphetamine challenge increased amygdala activation during processing of fearful and angry faces in healthy adults.9 The latter finding was considered to reflect the neural basis underlying the anxiogenic effects of stimulants, but it is interesting to speculate whether this finding offers a rationale for using stimulants to treat a subgroup of individuals characterized by lack of empathy, too little anxiety in situations in which anxiety is appropriate (e.g., individuals with CU traits), and corresponding proactive aggression. Certainly, the data cited here do not provide a solid enough justification for such an
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
EDITORIAL
approach. However, delineating the neurobiological distinctiveness of youth with and without CU traits and using biomarker-informed strategies to predict treatment response in this population could be an important and potentially fruitful area for future research. There are several clinical take-home points to emphasize. First, proactive aggression rarely occurs alone in clinically referred preadolescent youth; rather, it almost always is accompanied by reactive aggression. When proactive aggression is present, it generally signals increased severity of aggression. Second, stimulant treatment is likely to produce improvement in ADHD and aggression, and an optimized approach to titration using multiple stimulant classes and doses greatly improves the likelihood of response. Third, children with proactive aggression and CU traits can be treated successfully in many cases. The investigators indicate that “optimized stimulant therapy warrants strong consideration as firstline intervention for children who present with significant aggression whether or not informants perceive that such behaviors are often volitional.” However, the extent to which improvement was due to medication versus behavior therapy cannot be determined from this study. It is likely that concomitant use of parent-based behavior therapy will add to the degree of improvement observed with stimulants. Moreover, behavioral therapy alone might produce improvement. That was not tested in this study. There will likely be different opinions as to whether it is good or bad news that CU traits did
not moderate response to stimulant treatment in preadolescent youth with ADHD and aggression. The good news is that a group previously thought to be treatment resistant can in fact be treated with some degree of success. The bad news is that the presence of CU traits in this population did not add much over severity in predicting treatment response, and the failure of CU traits to predict differential treatment response could be seen as decreasing the clinical utility of this construct. Nevertheless, the wealth of data supporting the clinical and neurobiological distinctiveness of individuals with CU traits is compelling—although, as this study points out, operationalizing the constructs and fully understanding their meaning is challenging, particularly in children. It is hoped that development of external validators of clinical diagnosis and biomarker-driven treatment approaches will help resolve some of the issues raised by this interesting and very well-done article. & Accepted September 26, 2013. Dr. Newcorn is with Icahn School of Medicine at Mount Sinai. Disclosure: Dr. Newcorn has received research support from Eli Lilly and Co., Ortho-McNeil-Janssen, and Shire. He has served as an advisor and/or consultant to Alcobra, BioBehavioral Diagnostics, Enzymotec, GencoSciences, Neos Therapeutics, Otsuka, Shionogi, Sunovion, and Shire. Correspondence to Jeffrey H. Newcorn, M.D., One Gustave L. Levy Place, Box 1230, New York, NY 10029; e-mail: jeffrey.newcorn@ mssm.edu 0890-8567/$36.00/ª2013 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2013.09.010
REFERENCES 1. Frick PJ, Ray JV, Thornton LC, Kahn RE. Can callous-unemotional traits enhance the understanding, diagnosis, and treatment of serious conduct problems in children and adolescents? A comprehensive review. Psychol Bull. 2013. 2. Pardini D, Stepp S, Hipwell A, Stouthamer-Loeber M, Loeber R. The clinical utility of the proposed DSM-5 callous-unemotional subtype of conduct disorder in young girls. J Am Acad Child Adolesc Psychiatry. 2012;51:62-73. 3. de Wied M, van Boxtel A, Matthys W, Meeus WJ. Verbal, facial and autonomic responses to empathy-eliciting film clips by disruptive male adolescents with high versus low callous-unemotional traits. Abnorm Child Psychol. 2012;40:211-223. 4. Marsh AA, Finger EC, Mitchell DG, et al. Reduced amygdala response to fearful expressions in children and adolescents with callous-unemotional traits and disruptive behavior disorders. Am J Psychiatry. 2008;165:712-720. 5. Marsh AA, Finger EC, Fowler KA, et al. Reduced amygdalaorbitofrontal connectivity during moral judgments in youths with
6.
7.
8.
9.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 12 DECEMBER 2013
disruptive behavior disorders and psychopathic traits. Psychiatry Res. 2011;194:279-286. Waschbusch DA, Carrey NJ, Willoughby MT, King S, Andrade BF. Effects of methylphenidate and behavior modification on the social and academic behavior of children with disruptive behavior disorders: the moderating role of callous/unemotional traits. J Clin Child Adolesc Psychol. 2007;36:629-644. 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. Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollack S. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry. 1997;54:1073-1080. Hariri AR, Mattay VS, Tessitore A, Fera F, Smith WG, Weinberger DR. Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology. 2002;27:1036-1040.
www.jaacap.org
1259
