Sleep-associated adverse events during the methylphenidate treatment of attention-deficit/hyperactivity disorder: A meta-analysis

Abstract

Objective: Sleep disturbances are a feature of attention deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate (MPH) treatment. We sought to clarify MPH-associated sleep problems and how studies are affected by confounding factors.

Data Sources: Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and FDA websites. Sources were searched from inception to August 2017.

Study Selection: We included blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings. This led to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3079 drug-exposed and 2606 placebo-treated patients.

Data Extraction: Two PhD reviewers reviewed each study for inclusion. Four PhD/PharmD reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author.

Results: We found increased pooled relative risks (RRs) for MPH-associated sleep-related AEs for insomnia, initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the MPH formulation studied. After correcting for confounding, we found significant differences among drugs. We show that the RR, and its interpretation, is constrained by the placebo AE rate.

Conclusions: Several types of insomnia and sleep problems are associated with MPH treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, we provide the field with a useful covariate for adjusting RR statistics.

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Identifiers

ORCID for Samuele Cortese: orcid.org/0000-0001-5877-8075

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