Adjunctive Antipsychotic Cuts Aggression in Kids With ADHD

Deborah Brauser

February 05, 2014

Adding a second-generation antipsychotic (SGA) to a basic treatment intervention consisting of a psychostimulant and behavioral parent training (PT) may decrease aggression in children with attention-deficit/hyperactivity disorder (ADHD), new research suggests.

A randomized study of 168 children clinically diagnosed with ADHD and having severe physical aggression showed that those who received a 9-week treatment plan of risperidone in addition to a psychostimulant and PT showed significant improvements on measures of both aggression and serious behavioral problems compared with those who received the stimulant plus PT only.

Lead author Michael G. Aman, PhD, emeritus professor of psychology and psychiatry at Ohio State University in Columbus, told Medscape Medical News that although the decrease in aggression after the addition of risperidone was "significant but modest," the findings are still important for families.

"These children entered the study with very significant disruptive behavior that really put them on a collision course with their families or communities or schools," said Dr. Aman.

"Our study simply showed that some children will show a moderate improvement after the addition of a second medication. But that might be the difference between being able to stay in their present class or school or having to move to a new place."

He noted in a release that the investigators conducted the study because they viewed the combination of ADHD and significant aggression as a serious situation.

"Although doctors have often used stimulants and antipsychotics together in recent years, we did not have good evidence until now that they would work more effectively when carefully staged and given together," he said.

The study was published in the January issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

High Aggression Scores

The Treatment of Severe Childhood Aggression (TOSCA) study enrolled 168 children between the ages of 6 and 12 years (76.8% boys; mean age, 8.9 years) with ADHD, a disruptive behavior disorder, a score of 3 or higher on the Overt Aggression Scale–M, a parent rating score of at least 27 (90th percentile) on the Disruptive–Total subscale of the Nisonger Child Behavior Rating Form (NCBRF), and a score of at least 4 for aggression on the Clinical Global Impressions–Severity (CGI-S) scale.

Of these children, 124 had oppositional-defiant disorder, and 44 had conduct disorder.

Dr. Michael Aman

All participants received titrated doses of a psychostimulant for 3 weeks while their parents received PT consisting of behavior management techniques. Osmotic Release Oral System (OROS) methylphenidate was the stimulant most used. However, if patients could not tolerate OROS or had problems swallowing pills, capsules of mixed amphetamine salts, dextromethylphenidate, or lis- dexamphetamine dimesylate sprinkled onto food could be used instead.

"If there was room for improvement," the children were then divided into 2 subgroups: the augmented treatment and the basic treatment groups (n = 84 in each).

For 6 weeks, risperidone was added to the augmented treatment group's regimen of PT plus stimulant (mean week-9 dose, 1.7 mg/day), and a matching placebo was added to the basic treatment group.

The primary outcome measure was changes on the parent-reported NCBRF Disruptive–Total subscale. Secondary outcomes included the parent-reported NCBRF Social Competence subscale and the Antisocial Behavior Scale (ABS), and the CGI–Improvement (CGI-I) scale.

Results showed that the augmented group had significantly greater improvements over time on the NCBRF Disruptive–Total subscale than did the basic group (P = .0016). In addition, the between-group differences stayed significant at the 9-week mark (P = .014).

The augmented group also had greater improvements on the NCBRF Social Competence (P = .005) and the ABS Reactive Aggression (P = .01) subscales, but not on the ABS Proactive subscale.

Full Clinical Implications Not Yet Clear

Although 79% of the augmented group were considered "very much improved" on the CGI-I vs 70% of the basic treatment group, these between-group differences were not considered statistically significant. There were also no significant differences on the CGI-S (72% rated as "normal/borderline/mildly ill" vs 59%, respectively).

Joseph C. Blader, PhD, from the Division of Child and Adolescent Psychiatry at the University of Texas Health Science Center in San Antonio, writes in an accompanying editorial that it appears that the initial 3 weeks of stimulant monotherapy for all the participants "did much of the heavy lifting toward the ultimate response" measured at week 9.

No serious adverse events (AEs) were reported. Significantly higher prolactin concentrations were found in the augmented group than in the basic group (36.0 μg/L vs 7.1 μg/L, respectively; P < .0001), as were more reports of gastrointestinal discomfort (16.4% vs 5%, P = .03).

On the other hand, trouble falling asleep was reported by significantly more of the basic treatment group (36.3% vs 19.2%; P = .02).

The investigators noted in the release that risperidone and the stimulant appeared to neutralize some of each other's potential side effects. "For instance, children in the augmented group did not seem to have as much trouble falling asleep once risperidone was added," they explained.

Overall, "our findings may be considered somewhat controversial because they appear to support the use of 2 drugs over 1 for treating children with aggression and disruptive behavior when things do not seem to be going well," said Dr. Aman.

"Many practitioners have been taught to 'keep things simple and safe' in their medical training. And in general, this is good advice."

However, he noted that in this population with severe aggression, families are often desperately looking for help. "If parent therapy plus stimulant treatment works, leave well enough alone. But if the scores bounce around, a second medication may be needed."

Still, the investigators point out that this trial was relatively brief and that there could be "possible subsequent waning of efficacy" of risperidone over time and a possibility of further problematic AES, such as weight gain or metabolic disturbances.

"The true implications of this study for informing clinical practice will be more fully realized when analyses of the 3-month follow-up assessment are completed," they write.

"Exceptionally Useful"

Dr. Blader writes in his editorial that it is understandable if clinicians' first reaction to hearing about this study is that it is about as needed as 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…make it exceptionally useful indeed," he writes, adding that it also "transcends" previous research in several ways.

"Volatile, impulsive children with brittle frustration tolerance who display persistent aggressive behavior are the dominant preadolescent group receiving mental health care," writes Dr. Blader.

However, "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."

He also applauds the trial's inclusion of meaningful thresholds of aggression, but notes that the magnitude of effect for the augmented group was moderate ― and writes that some clinicians may wonder whether cotherapy is worth the added expense and potential risk.

Still, Dr. Blader writes that the study's strategy of giving stimulant monotherapy for 3 weeks and then starting risperidone only if there is room for improvement is interesting; and the overall findings contribute "real data to formulate detailed treatment guidelines affecting the care of many thousands of children."

"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," he writes.

Although he notes that the investigators' not discussing ADHD symptom outcomes during the course of the trial was curious and that he hopes that they release that information in future reports, he praised both the trial and Dr. Aman.

"The study's first author has for decades been a true pioneer in psychopharmacologic research that has led to helping many youth," writes Dr. Blader.

The study authors report several financial relationships, including relationships with pharmaceutical companies; the full list can be found in the original article. Dr. Blader reports receiving research grant support from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, Abbott Laboratories, and Supernus Pharmaceuticals and that he has served as a consultant to Shire and Supernus.

J Am Acad Child Adolesc Psychiatry. 2014;53:47-60, 17-20. Full article, Editorial

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