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Re: Age-related changes in motor subtle signs among girls and boys with ADHD

Cole et al. described boys with attention-deficit hyperactivity disorder (ADHD) showing little age-related improvement in motor speed and subtle signs of motor function while girls with ADHD appear to improve at a comparable rate to normal girls. [1]

In this study, stimulant medication was omitted on the day of testing and the previous day. This is important because stimulant medication has been shown to reduce the rate of movements in children with ADHD performing cognitive tasks. [2,3] In addition, differential effects of methylphenidate and dexamphetamine on the motor activity levels of hyperactive children have been described. [2]

Despite the 24-hour wash-out period, the history of treatment with stimulant medication may be an important consideration. In this context it is vital because the therapeutic effect of stimulant medication is wearing off and there is a rebound period. This results in a measurable increase in hyperactivity which may persist overnight and until the first dose of medication is given the following day. [3]

This residual effect of stimulant medication could have affected the subjects’ performance during testing. Failure to match the groups of boys and girls for this confounder could account for the sex differences observed.

References

1. Cole W, Mostofsky S, Larson J, Denckla M, Mahone E. Age-related changes in motor subtle signs among girls and boys with ADHD. Neurology 2008;71:1514-1520.

2. Borcherding BG, Keysor CS, Cooper TB, Rapoport JL. Differential effects of methylphenidate and dextroamphetamine on the motor activity level of hyperactive children. Neuropsychopharmacology 1989;2:255-263.

3. Porrino LJ, Rapoport JL, Behar D, Ismond DR, Bunney WE Jr. A naturalistic assessment of the motor activity of hyperactive boys. II. Stimulant drug effects. Arch Gen Psychiatry 1983;40:688-693.

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Re: Reply from the authors

Drs. Poulton and Nanan discuss the impact of stimulant medication on motor function and the possibility of stimulant rebound contributing to the observed increase in neurological subtle signs among children with ADHD.

The relationship between stimulant rebound on variables measured by the Physical and Neurological Examination for Soft Signs (PANESS) will be an important area for future investigation. It will be crucial to distinguish spontaneous motor hyperactivity—as has been reported —from the atypical, involuntary movements (i.e., overflow, dysrhythmia) elicited during administration of the PANESS. [2,3]

While it is possible that stimulant rebound may contribute to atypical motor behaviors, we believe that this was an unlikely confounder in our sample. More recent studies of stimulant rebound, based on extended release methylphenidate and mixed amphetamine salts (Adderall), suggest that rebound typically occurs late day or early evening after a same-day morning dose of the medication. [4] The half-life of methylphenidate is approximately 3-4 hours, while the half-life of Adderall is 6 hours. [5,6]

In our study, the last dose of medication was typically administered at least 36 (and often 48) hours prior to testing, likely allowing for sufficient time for any confounding rebound to have occurred. In addition, because a high proportion of our testing was completed during the summer months, approximately 40% of the children in our sample were not taking stimulant medications at the time of assessment, while approximately 20% were medication naïve.

Valid measurement of stimulant rebound can be challenging. Johnston et al. found ratings of stimulant rebound to be variable (i.e., occurring on one rating but not another). [7] It has also been found that the rebound effects reported by parents of children taking Adderall were similar to those reported by parents of children on placebo, suggesting that some reports of rebound may be due to reporter bias rather than an actual increase in symptoms. [8]

In a systematic investigation of rebound effects among children taking short-acting stimulants—primarily methylphenidate—using objective observations of behavior, worsening of baseline symptoms occurred in less than 21% of the sample, while “serious and consistent worsening” occurred in less than 10%. [6]

References

4. Carlson GA, Kelly KL. Stimulant rebound: How common is it and what does it mean? J Am Acad Child Adolesc Psychopharm 2003;13:137-142.

5. Patrick KS, Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder. Human Psychopharm 1997;12:527-546.

6. Pelham WE, Aronoff HE, Midlam JK et al. A comparison of Ritalin and Adderall: Efficacy and time-course in children with attention-deficit/ hyperactivity disorder. Pediatrics 1999;103:e43.

7. Johnston C, Pelham WE, Hoza J, Sturges J. Psychostimulant rebound in attention deficit disordered boys. J Am Acad Child Adolesc Psychiatry 1988;27:806-810.

8. Pliszka SR, Browne RG, Olvera RL, Wynne SK. A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/ hyperactivity disorder. J Am Acad Child Adolesc Pscyhiatry 2000;39:619-626.