Autism spectrum disorder

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Journal of Autism and Developmental Disorders https://doi.org/10.1007/s10803-020-04705-y

L E T T E R TO T H E E D I TO R

Insomnia and Treatment Strategies: Improving Quality of Life in Children with Autism Spectrum Disorder

Bárbara Virginia Vitti‑Ruela1 · Vinícius Dokkedal‑Silva2 · Priscila Kalil Morelhão2 · Sandra Doria Xavier2 · Sergio Tufik2 · Monica Levy Andersen2

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Dear Editor, Autism spectrum disorder (ASD) is a complex develop-

mental disorder that involves impairments in social com- munication and interaction, sensory abnormalities and restricted and repetitive behaviors (Vahia 2013). Insomnia is commonly observed in children with ASD, reaching a prevalence as high as 60–86%, two to three times greater when compared to typically developing (TD) children (Rich- dale and Schreck 2009; Posar and Visconti 2020). The main cause of sleep disorders include the interaction of several factors, such as poor sleep hygiene and abnormalities in the melatonin system (Mazurek and Sohl 2016; Gagnon and Godbout 2018).

A systematic review assessing objective and subjective sleep studies in individuals with ASD found a significantly higher bedtime resistance, sleep onset delay, sleep anxiety, night awakenings, parasomnias, sleep-disordered breathing, daytime sleepiness, sleep onset latency (in min), restora- tive value of sleep and general sleep problems (Diaz-Roman et al. 2018; Mazurek and Sohl 2016). Moreover, sleep depri- vation effects seem to be more intense in ASD children than in TD ones (Mazurek and Sohl 2016). As a consequence of these sleep problems there is a worsening of behavior, which may include aggression, irritability, inattention and hyper- activity (Mazurek and Sohl 2016; Posar and Visconti 2020).

The neurological mechanisms underlying insomnia in ASD are not yet fully understood. However, it is known that sleep plays an important role in neurological development, since many of the processes involved occur at ages when

sleep is the predominant brain state (Wintler et al. 2020). The balance between excitatory and inhibitory neurotrans- mission, especially with regard to the paradoxical mecha- nism of GABA, seem to influence the pathophysiology and be related to the dysfunction of the ASD network (Wintler et al. 2020).

One possible mechanism involved in insomnia in ASD children could be sensorial dysregulation, which is very fre- quent. Reynolds et al. (2011) found a higher prevalence of atypical sensory behaviors and sleep disturbances in children with ASD aged between 6 and 12  years when compared to TD. As suggested by Souders et  al. (2017), sleep dif- ficulties may be connected to localized problems in differ- ent sensory areas and a higher sensory threshold (that is, a reduced sensibility to sensory stimuli) would be related to better sleep. In this sense, a focus must be given to reduc- ing sensory hyper-reactivity by making alterations in the bedroom, which include reduction of environmental stimuli and appliance of calming strategies (Souders et al. 2017).

A case–control study has shown that there might be an interruption of sleep homeostasis in ASD children, leading to reduced sleep pressure and consequently problems in ini- tiating and maintaining sleep, besides being correlated with the severity of the disorders presented (Arazi et al. 2019). This characteristic is expressed by weaker delta power dur- ing slow wave sleep (SWS) and less N3 sleep during the first 2 h of sleep (Arazi et al. 2019).

ASD may also be associated with a dysregulation of the circadian cycle, marked by a disturbance in melatonin pro- duction, which can contribute to sleep disturbances, such as insomnia (Gagnon and Godbout 2018). A possible strategy to reduce this sleep problem could be to administer mela- tonin to help initiate and maintain sleep. Melatonin acts by activating 2 high-affinity membrane receptors MT1 and MT2, which are distributed, mainly, by the brain and spinal cord (Gagnon and Godbout 2018; Atkin et al. 2018). Mela- tonin is already used as a treatment for insomnia in ASD and

* Monica Levy Andersen [email protected]

1 Faculdade de Medicina de Marília, Avenida Monte Carmelo, 800, Marília, Brazil

2 Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 925, Vila Clementino, São Paulo 04024-002, Brazil

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evidence suggests that it may also be useful for treatment of comorbidities that contribute to further impairment of sleep (Gagnon and Godbout 2018; Atkin et al. 2018).

Whereas melatonin acts only by modifying time to facili- tate sleep and has no effect on sleep architecture, another possible treatment could be the use of the Z-drugs (zolpi- dem, zaleplon, zopiclone and eszopiclone) (Atkin et  al. 2018). Among the Z-drugs, zolpidem and zaleplon alter the structure of sleep and reduce latency for the onset of sleep. Zolpidem also increases total sleep time (Sukys-Claudino et al. 2010). The Z-drugs are FDA-approved for insomnia disorders and act as positive allosteric modulators at the GABA binding site, potentiating the inhibitory effect of GABA. These drugs have a greater affinity for the alpha 1 receptor, which seems to be related to sleep (Atkin et al. 2018). However, careful attention should be paid to the pos- sible side effects of these drugs, which include coordination and cognitive impairment, tolerance and abuse. (Atkin et al. 2018). Caution is also needed regarding the administration of these drugs in patients with ASD, since a long-term treat- ment may be necessary and Z drugs are generally used for a restricted period. To the best of our knowledge, no investiga- tion of the efficacy of Z-drugs in the treatment of insomnia in ASD children has been carried out. Randomized clinical trials should be conducted to verify the safety, efficacy and possible side effects of Z-drugs in the treatment of these patients.

Combining the use of Z-drugs with melatonin might help to reduce the most common sleep disturbance presented in ASD, insomnia (Richdale and Schreck 2009; Mazurek and Sohl 2016). We believe that further randomized controlled trials should be carried out to assess the possible interactions and benefits of the polytherapy with Z-drugs and melatonin. As treatment with Z-drugs may have potential side effects, it is worth investigating if their use with melatonin might allow a reduction in dosage and improve sleep outcomes while reducing or avoiding these side effects.

Given the need to deliver appropriate treatment for insomnia in children with ASD, we would like to highlight the importance of behavioral and pharmacological treatment strategies, especially those including Z-drugs, melatonin and sensory profile interventions aimed at improving the qual- ity of life of these individuals and ameliorating behavio- ral symptoms. Nevertheless, clinical trials are necessary to investigate the effect of these medications as an intervention measure in children with ASD.

Acknowledgments Our studies are supported by grants from the Asso- ciação Fundo de Incentivo à Pesquisa (AFIP). M.L.A. and S.T. are CNPq fellowship recipients.

Author Contributions BVV-R was responsible for the conception and writing of the manuscript and the literature search. VD-S participated in the writing and revision of the manuscript. PKM contributed to the

conception of the manuscript and participated in its writing and revision. SDX revised the manuscript and contributed to the literature search. ST has supervised the production of the manuscript and provided funding. ML Andersen was the main supervisor of the manuscript and participated in its revision.

Compliance with Ethical Standards

Conflict of interest The authors declare that they have no conflict of in- terest.

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