Treatment of sleep disorders in youth with ADHD: what is the evidence from randomised controlled trials and how should the field move forward?

KEYWORDS:

• ADHD
• sleep
• randomised controlled trials
• evidence base
• treatment

Sleep complaints are reported in about 50–70% of individuals referred or treated for attention-deficit/hyperactivity disorder (ADHD) [1], one of the most commonly diagnosed neurodevelopmental disorders with complex neurobiological underpinnings [2]. The most commonly reported sleep disturbances include common, aspecific sleep problems, such as bedtime resistance, difficulty falling asleep, and night awakenings, as well as specific sleep disorders, in particular, restless legs syndrome, periodic limb movement disorder, and sleep disordered breathing [3].

Sleep dysfunction in individuals with ADHD is underpinned by a multifactorial etiopathophysiology [4,5]. From a clinical standpoint, it is fundamental to screen for and appropriately treat sleep disturbances associated with ADHD because they are an important source of distress for patients and their families and they can also worsen or mimic daytime ADHD symptoms. In 2013, Cortese et al. published the summary of an expert consensus on the management of sleep disturbance in children and adolescents with ADHD [5]. At that time (studies published up to 31 October 2012 were reviewed), the expert group was able to find only a limited number of randomized controlled trials (RCTs) testing the efficacy of pharmacological or non-pharmacological interventions for sleep disturbance in youth with ADHD. More specifically, they found only one pilot RCT (plus preliminary analyses from another one) supporting behavioral interventions for insomnia, two RCTs showing positive effects of melatonin for sleep-onset delay not caused by psychostimulant treatment, and one RCT for restless legs syndrome in youth with ADHD. They also found another RCT showing that the addition of melatonin is effective in decreasing sleep onset delay caused by psychostimulants. Finally, two nonrandomized trials supported the use of adenotonsillectomy to reduce ADHD-like symptoms in children with sleep disordered breathing.

Has the evidence base become more solid since then? Certainly, based on a comprehensive search in PubMed, important RCTs, testing the efficacy of pharmacological or non-pharmacological interventions for sleep problems in youth (6–18 years old) with ADHD, have been published since.

With regard to non-pharmacological treatments, the full study results by Corkum et al. [6], for which only preliminary analyses were available when Cortese et al. reviewed the literature on 2012, have been published. This RCT aimed to assess the efficacy of a five-session manualized behavioral intervention for sleep problems in children with or without ADHD. The study showed that sleep of children randomized to the study intervention was rated as significantly improved by parents, compared to the control group assigned to waitlist, at postintervention (2 months) and 6-month follow-up. Additionally, actigraphic evaluation confirmed a significant reduction of sleep onset latency, albeit without a significant increase in total sleep time, in the active treatment group.

Another important RCT, conducted by Hiscock and colleagues [7], assessed the efficacy of a short intervention, based on sleep hygiene practices and behavioral strategies delivered during two fortnightly consultations and a follow-up telephone call. Compared to those assigned to usual care, children randomized to the active intervention presented with significantly fewer moderate and severe sleep problems (as reported by the caregiver) after 3 months (estimated number needed to treat, NTT: 3.9) and 6 months (estimated NTT: 7.8).

Keshavarzi et al. [8] confirmed the efficacy of behavioral sleep interventions, based on parent training, in another RCT in children with ADHD. At the end point (12 weeks), sleep problems of children whose parents participated in a sleep training behavioral program were rated as significantly improved, compared to sleep problems of children whose parents were randomized to the control intervention (one session on sleep hygiene).

While the results of these RCTs on non-pharmacological interventions are encouraging, two pharmacological RCTs published since 2012 are substantially negative. Sangal et al. [9] evaluated the efficacy and safety of eszopiclone in a 12-week, randomized, double-blind, placebo-controlled trial in children with ADHD. Compared to placebo, eszopiclone failed to be significantly more efficacious in any of the outcomes (latency to persistent sleep and wake time after sleep measured via polysomnography, Clinical Global Impression Parent/Caregiver and Child scales, and the Conners’ ADHD rating scales). In the second trial, Ferri et al. [10] assessed the effect of L-Dopa on leg movements during sleep (that may impact on sleep quality and quantity) in a group of children with ADHD and typically developing controls. While, compared to placebo, L-Dopa was associated with a significant reduction of sleep latency, all other polysomnographic parameters remained substantially unchanged at study end point.

We are also aware of an ongoing N-of-1 randomized controlled trial to assess the effects of melatonin on sleep in youth with ADHD treated with psychostimulants [11]. Finally, although there have been additional studies, the impact of surgery for ADHD-like symptoms in children with ADHD, we could not retrieve any RCT specifically focusing on this.

Overall, as it appears evident, although remarkable research efforts have been made over the past years, the body of evidence informing the treatment of sleep disorders associated with ADHD remains still limited.

How to move the field forward? Besides standard efficacy RCTs, we need pragmatic trials, aiming to investigate whether a treatment has clinically meaningful effects in the ‘real world.’ Pragmatic trials should also inform how best to sequence different treatment strategies and how to target them according to the specific sleep phenotypes of patients with ADHD. It will be particularly relevant for the future trials to include patients seen in routine care, rather than highly selected samples of patients. The study protocol recently published by van der Zweerde et al. [12], focusing on is an example of how the field of sleep medicine is moving toward pragmatic trails.

Untested strategies provide exciting opportunities for the future. More specifically, in terms of non-pharmacological treatments, enhancement of CBT-sessions with phone calls and new technological approaches such as telemedicine and internet-delivered psychological treatment has already proved to be effective in adults with insomnia [13], and could be an attractive option for youth with ADHD, especially adolescents. Additionally, other treatment modalities, such as light therapy, remain largely unexplored and could be of interest in the light of the circadian rhythm dysfunction and melatonin secretion delay reported in individuals with ADHD [5]. Furthermore, we deem particularly important to target sleep disturbance in preschoolers at risk for ADHD, which would provide insights on possible causal relationship between early sleep disturbance and later ADHD symptoms development [14], and potentially pave the way for important preventive strategies for ADHD.

As for pharmacological treatments, we need additional evidence on commonly used compounds (including melatonin) to better determine their efficacy, tolerability, effective dose range, ideal timing of administration, and recommended duration of treatment. Additionally, novel agents such as orexin antagonists, which act also on brain circuits involved in eating, would be an appealing option to test, given the increasing awareness on the alterations not only of sleep, but also of feeding/eating patterns in ADHD [4,15]. Finally, it will be interesting to explore possible gender effects in the response to treatment.

We look forward to the next generation of RCTs on the treatment of sleep disorders in youth with ADHD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.