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Abstract

  1. Top of page
  2. Abstract
  3. Clinical implications
  4. Acknowledgement
  5. References

This randomized clinical trial of methylphenidate in children with intellectual disability (ID) by Simonoff et al. (2013) advances the field in several ways useful to clinicians. The three-figure widely representative sample more definitively confirms findings previously reported from smaller studies and studies with a differently selected sample. The medium placebo-controlled effect size found is in line with previous more tentative suggestions for ID, such as those summarized by Aman et al. This sample, selected for ID but coincidentally including some children with autism (a third of the sample), nicely complements the RUPP Autism Network (2005) study of 72 children with autism, most of whom also had ID (mean IQ 62.6, range 16-135). Similar effect was found in both studies, suggesting that one might expect a medium effect widely in the intellectual & developmental disability (IDD) population, with a 40-50% response rate.

However, the rate of intolerable side effects was considerably lower in this trial (5/61, 8%) than in the RUPP Autism trial (13/72, 18%). This could be due to children with autism being more sensitive to the side effects than other children with ID, but it could also be a difference in design. Simonoff et al. used a clinical titration, presumably with dose adjustments weekly. The RUPP trial, in an initial run-in week, gave 2 days of each dose in ascending fashion, and this accounted for six of the dropouts for intolerability, possibly due to the rapid escalation. Then the 4-week crossover had some orders of condition going from low to high dose or from placebo to medium dose. This may also have contributed to the additional seven dropouts in the crossover phase. This difference between studies is encouraging, because the Simonoff titration strategy is more similar to what is actually done (or should be done) clinically. Nevertheless, even 8% is twice the rate of intolerable side effects for typically developing children with attention-deficit hyperactivity disorder (ADHD; MTA Cooperative Group, 1999). It would be interesting to know how many of the five dropouts for intolerable side effects in the Simonoff et al. study had autism. (By the way, it is an interesting coincidence that 18% of the children in the Simonoff study had ‘none’ selected as their final dose in the clinical trial.)

Another interesting contrast is that in this study the effect size for teacher ratings (d = 0.52) is larger than for parent ratings (d = 0.39), a pattern similar to that of typically developing children (albeit at a lower level), whereas in the RUPP Autism study, the effect by parent ratings (d = 0.89) was larger than by teacher rating (d = 0.48). This could be due to the differences in school placement or situation-specific responses by children with autism. One might wonder if the lower teacher ratings of improvement in the RUPP study could be due to a ceiling effect from teachers in the RUPP study rating children slightly less severe at baseline than parents did. However, such is not the case: teachers in the Simonoff study rated children even less severe than either their parents or RUPP teachers did. (Parents in both studies rated children at baseline about 32 on the Aberrant Behavior Checklist hyperactivity subscale, with RUPP teachers rating about 29 and Simonoff teachers rating about 21 at baseline.) Actually, the pattern difference in improvement ratings between the two studies seems to be due to a difference in parent ratings of improvement, not teacher ratings. If teacher ratings of improvement, similar between the two studies, are accepted as ‘gold standard,’ a question arises about parent ratings: does having autism spectrum disorder in addition to ID moderate the home behavior response to methylphenidate? It would be interesting if Simonoff and colleagues could compare effect sizes and response rates (and intolerable side effect rates) between their autistic subgroup and the rest of their sample to explore this issue.

A possible explanation of some of the outcome differences might be the diagnostic inclusion screen. The RUPP Autism study used DSM-IV ADHD criteria while the Simonoff et al. study used ICD-10 hyperkinetic disorder criteria. In the typically developing MTA sample selected for combined type ADHD by DSM-IV criteria (MTA Cooperative Group, 1999), only about one-fourth (145 of 589) also met criteria for hyperkinetic disorder or hyperkinetic conduct disorder (Santosh et al., 2005). Interestingly, this hyperkinetic subgroup had a substantially larger methylphenidate favorable response than the remaining MTA children, which might lead us to expect a larger effect size in the Simonoff study than in the RUPP Autism study, which was not found.

The Simonoff et al. study sample size (122) allowed a moderator analysis by IQ to test the previous suspicion of an association of IQ with benefit. This was not found. However, as the authors point out, this may be due to not having any subjects with IQ 70 or higher, as were included in the previous studies. Carrying this observation a step further, it does appear there is an association of IQ with favorable response, because the effect sizes and response rate that this study confirms for IDD are considerably below those routinely reported for typically developing children of normal IQ with ADHD, confirming the association across those broad categories. It is interesting that the RUPP Autism Network sample, with IQ ranging up to 135 (mean 62.6) showed a considerably larger effect size by parent ratings, but not teacher ratings, than the Simonoff study, with IQ < 70 (mean 53). This difference in parent-rated improvement with similar teacher-rated improvement raises an interesting speculation: could the IQ moderation suspected by Aman et al. based on parent ratings have arisen from parents of brighter children, presumably also brighter themselves, being better able to detect improvement?

Clinical implications

  1. Top of page
  2. Abstract
  3. Clinical implications
  4. Acknowledgement
  5. References

What are the practical conclusions for clinicians? Putting the Simonoff et al. findings together with other relevant literature, clinicians could use the following guidelines:

  • Patients with IDD are not as likely to have a good response to a stimulant as typically developing children, and are more likely to have intolerable side effects. There is a hint that they do not tolerate rapid dose escalation as well as typically developing children do. Therefore, when prescribing a stimulant, the monitoring and titration must be more careful and upward adjustments more cautious than with typically developing children.
  • Nevertheless, the response rate of 40–50%, although lower than the 70% expected in typically developing children, makes a cautious trial worthwhile.
  • Although the high dose of methylphenidate (1.5 mg/kg/day) was settled on as final for 45% of the children, there were also substantial percents for whom low dose (13%, 0.5 mg/kg/day) and medium dose (23%, 1 mg/kg/day) were the final dose–and even ‘none’ for 18%. Therefore, to avoid missing the optimal individualized dose, it is important to start with the smallest dose and titrate up weekly with careful assessment of results from both home and school informants.
  • The best studied stimulant in this population is methylphenidate, making it a logical first choice. However, there is no reason to think that amphetamine would be less effective. Because studies in typically developing children show incomplete overlap, with some patients responding better to one, others to the other (Arnold, 2000), it would be logical to try amphetamine if methylphenidate is not satisfactory. However, atomoxetine (Arnold et al., 2006) and guanfacine also have some reported benefit in this population. As a last resort, antipsychotic agents, such as risperidone, appear to ameliorate hyperactivity as well as irritability, at least in those with autism (RUPP Autism Network, 2002).
  • Because children with IDD may have swallowing difficulty, extended-release formulations that have to be swallowed whole may be problematic. However, the bead formulations can be sprinkled onto favorite soft food.
  • Because of idiosyncratic dietary preferences, many children with IDD may have an imbalance that could benefit from RDA/RDI multivitamin/mineral supplement, especially if appetite is suppressed by a stimulant. Similarly, modest amounts of mercury-free omega-3 polyunsaturated fatty acid may be helpful as an adjunct.

Simonoff and colleagues are to be congratulated for undertaking and completing such a large and difficult but useful study.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Clinical implications
  4. Acknowledgement
  5. References

This commentary article was invited by JCPP Editors and while not subject to formal peer review, was reviewed internally and provided to the authors of Simonoff et al. for formal response (see: doi: 10.1111/jcpp.12098 [http://onlinelibrary.wiley.com/doi/10.1111/jcpp.12098/full]). D.A. has disclosed research funding from CureMark, Forest, Lilly, & Shire, advisory board honoraria from Biomarin, Novartis, Noven, Roche, Seaside Therapeutics, & Shire, consulting honoraria from Tris Pharma, and travel support from Noven.

References

  1. Top of page
  2. Abstract
  3. Clinical implications
  4. Acknowledgement
  5. References
  • Aman, M.G., Buican, B., & Arnold, L.E. (2003). Methylphenidate treatment in children with borderline IQ and mental retardation: Analysis of three aggregated studies. Journal of Child and Adolescent Psychopharmacology, 13, 2940.
  • Arnold, L.E. (2000). Methylphenidate vs. amphetamine: Comparative review. Journal of Attention Disorders, 3, 200211.
  • Arnold, L.E., Aman, M.G., Cook, A.M., Witwer, A.N., Hall, K.L., Thompson, S., & Ramadan, Y. (2006). Atomoxetine for hyperactivity in autism spectrum disorders: Placebo-controlled crossover pilot trial. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 11961205.
  • MTA Cooperative Group. (1999). A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Archives of General Psychiatry, 56, 107386.
  • Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. (2002). Randomized clinical trial of risperidone for irritability in autism. New England Journal of Medicine, 347, 314321.
  • Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. (2005). A randomized controlled crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Archives of General Psychiatry, 62, 12661274.
  • Santosh, P.J., Taylor, E., Swanson, J., Wigal, T., Chuang, S., Davies, M., Greenhill, L., … & Posner, M. (2005). Refining the diagnoses of inattention and overactivity syndromes: A reanalysis of the Multimodal Treatment study of attention deficit hyperactivity disorder (ADHD) based on ICD-10 criteria for hyperkinetic disorder. Clinical Neuroscience Research, 5, 307314.
  • Simonoff, E., Taylor, E., Baird, G., Bernard, S., Chadwick, O., Liang, H., … & Jichi, F. (2013). Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. Journal of Child Psychology and Psychiatry, 54, 527535.