Abstract
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Barrett et al. perform a much-needed review of the literature concerning pharmacological remedies for sleep disturbances associated with ADHD in children, and reach a sobering conclusion: a “paucity of evidence” for the effectiveness of medication treatments. Their well-designed study highlights not only the inconclusive nature of published studies but also the dearth of relevant research in an area that clinicians understand to be of great import to patients and their families. The authors' suggestion to the practitioner is sound: “Priority should be given to sleep hygiene education and optimizing the stimulant or non-stimulant treatment of ADHD.” But perhaps more intriguing for future inquiry is the question of what causes the phenomena of sleep disturbances in this population. Is it “an adverse effect of pharmacological treatment,” Barrett et al. wonder, “an alternative epiphenomenon stemming from core ADHD symptoms,” “a psychiatric comorbidity,” or “a combination”? This article suggests a path forward even as it cautions us to treat core symptoms with therapies that have a clear evidence base.
Are there biomarkers that indicate a tendency towards impairing side-effects from psychostimulant treatment for ADHD? This is the question posed by Johnson et al., and they focus on variation in the CES1 gene, which codes for “the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate.” Their findings are quite interesting—a link between certain variations and the occurrence of sadness as a side effect of methylphenidate (MPH) treatment. And the authors' keen reasoning opens up possibilities for future treatment development, particularly more targeted therapies. As they cautiously note, “the increase in sadness as a side-effect of MPH in the younger children probably relates to induced alterations in the noradrenaline and dopamine systems.”
Happily, Markowitz et al. take up this very issue in a wide-ranging investigation of the MPH homolog isopropylphenidate (IPH). These two articles reward close study together, particularly as Markowitz and his co-authors developed IPH specifically for its resistance to “CES1-catalyzed hydrolysis.” Through a remarkably thorough series of in vitro and in vivo assays comparing MPH and IPH's effects on dopamine, norepinephrine, and serotonin uptake, in addition to rat locomotor activity, the authors make a solid case for further research into this novel compound.
Finally, I would like to highlight a welcome and rigorous addition to the literature of schizophrenia and antipsychotic treatment from Stentebjerg-Olesen et al. The authors believe they have completed “the first study that demonstrated the validity of the early response paradigm in a naturalistically treated pediatric sample of mostly AP-naıve youth and those with PsyNOS,” and determined that early response indeed predicts a stable history of treatment response. More soberly, their research shows that older age at treatment onset and the presence of extrapyramidal symptoms predicts poor response in the future, highlighting both the need for early intervention and the development of better pharmacological treatments for psychotic disorders.