Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments
Abstract
:1. Introduction
2. Materials and Methods
3. Non-pharmacological Interventions
3.1. Parent-Based Sleep Education
3.2. Behavioral Interventions
- Extinction. Also known as “planned ignoring”, it is the most widely studied behavioral strategy, in which the caregiver ignores all the “undesirable sleep behaviors”—such as crying—after placing the child in bed, so as to remove reinforcement for these behaviors and promote self-settling [38]. This approach (standard extinction) has been found to reduce several sleep problems among children with ASD, including night-time awakenings, co-sleeping, sleep latency, and bedtime resistance [39,40,41]. Variants of extinction are “gradual extinction” and “extinction with parental presence”. Gradual extinction differs from the standard because the parents ignore bedtime disruption just for a predetermined amount of time, before engaging with the child [40]. Gradual extinction has also been found to reduce sleep disturbances and co-sleeping; however, more research is needed on this behavioral strategy [40]. According to the strategy of extinction with parental presence, the caregiver remains in the child’s room with little or no interaction [42].
- Extinction. Also known as “planned ignoring”, it is the most widely studied behavioral strategy, in which the caregiver ignores all the “undesirable sleep behaviors”—such as crying—after placing the child in bed, so as to remove reinforcement for these behaviors and promote self-settling [38]. This approach (standard extinction) has been found to reduce several sleep problems among children with ASD, including night-time awakenings, co-sleeping, sleep latency, and bedtime resistance [39,40,41]. Variants of extinction are “gradual extinction” and “extinction with parental presence”. Gradual extinction differs from the standard because the parents ignore bedtime disruption just for a predetermined amount of time, before engaging with the child [40]. Gradual extinction has also been found to reduce sleep disturbances and co-sleeping; however, more research is needed on this behavioral strategy [40]. According to the strategy of extinction with parental presence, the caregiver remains in the child’s room with little or no interaction [42].
- Scheduled awakenings. Strategy used to reduce episodes of disorders of arousal, such as sleep terrors, which requires the child to be awoken before the usual occurrence of the sleep terror episode, in order to reduce the fearful response [37,42]. This behavioral intervention has also been proven to be effective in increasing TST [42].
- Bedtime fading. Putting children to bed before the time they effectively fall asleep (sleep-onset time) increases the chances of bedtime resistance. Therefore, in this procedure the child is initially put to bed 30 min later than his/her average sleep-onset time. Then bedtime is gradually anticipated by 30 min every few days, until reaching the desired bedtime [40].
- Stimulus fading. This strategy involves the parent gradually increasing the distance between himself/herself and the child, until he/she can fall asleep, so as to specifically reduce co-sleeping [43].
- Chronotherapy. Bedtime is gradually delayed over time, to “re-set” the circadian rhythm and improve early-morning awakenings, sleep latency and night awakenings [40].
- Bedtime “pass”. A bedtime pass is a card or any equivalent object given to the child at bedtime that may be exchanged for one “free trip out of bed” or other forms of parental consolation after bedtime. If the bedtime pass has already been used, the parent should rapidly take the child back to bed. This kind of intervention can be used to teach the child to self-soothe and stay in bed in case of difficult sleep onset or frequent night awakenings [5,18].
- Positive reinforcement. This type of intervention uses rewards to promote the desired behaviors. Rewards are typically provided for the child upon awakening in the morning [44,45,46], though sometimes reinforcements may be provided during the sleep-onset period in the form of social attention for demonstrating sleep compatible behaviors [47].
3.3. Other Interventions
3.3.1. Weighted Blankets and Vests
3.3.2. Sound-To-Sleep (STS) Mattress
3.3.3. Massage
3.3.4. Aromatherapy
3.3.5. Yoga
3.3.6. Sport and Physical Activity
4. Oral Over-the-Counter Medicines
4.1. Melatonin
4.2. Antihistamines
4.3. Tryptophan/5-Hydroxytryptophan
4.4. Carnosine
4.5. Iron
4.6. Vitamin D
4.7. Multivitamin and Mineral Supplements
4.8. Herbal Remedies
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Lai, M.-C.; Lombardo, M.V.; Baron-Cohen, S. Autism. Lancet 2014, 383, 896–910. [Google Scholar] [CrossRef]
- Carmassi, C.; Palagini, L.; Caruso, D.; Masci, I.; Nobili, L.; Vita, A.; Dell’Osso, L. Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop. Front. Psychiatry 2019, 10, 366. [Google Scholar] [CrossRef]
- Souders, M.C.; Zavodny, S.; Eriksen, W.; Sinko, R.; Connell, J.; Kerns, C.; Schaaf, R.; Pinto-Martin, J. Sleep in Children with Autism Spectrum Disorder. Curr. Psychiatry Rep. 2017, 19, 34. [Google Scholar] [CrossRef]
- Klukowski, M.; Wasilewska, J.; Lebensztejn, D. Sleep and gastrointestinal disturbances in autism spectrum disorder in children. Dev. Period. Med. 2015, 19, 157–161. [Google Scholar]
- Grigg-Damberger, M.; Ralls, F. Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders. Curr. Opin. Pulm. Med. 2013, 19, 616–625. [Google Scholar] [CrossRef] [PubMed]
- Henderson, K. Policies and Practices Used by States to Serve Children with Autism Spectrum Disorders. J. Disabil. Policy Stud. 2011, 22, 106–115. [Google Scholar] [CrossRef]
- Sikora, D.M.; Johnson, K.; Clemons, T.; Katz, T. The relationship between sleep problems and daytime behavior in children of different ages with autism spectrum disorders. Pediatrics 2012, 130 (Suppl. 2), S83–S90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cohen, S.; Conduit, R.; Lockley, S.W.; Rajaratnam, S.M.; Cornish, K.M. The relationship between sleep and behavior in autism spectrum disorder (ASD): A review. J. Neurodev. Disord. 2014, 6, 44. [Google Scholar] [CrossRef] [Green Version]
- Shui, A.M.; Katz, T.; Malow, B.A.; Mazurek, M.O. Predicting sleep problems in children with autism spectrum disorders. Res. Dev. Disabil. 2018, 83, 270–279. [Google Scholar] [CrossRef]
- Howlett, M.; Jemcov, A.; Adams, A.; Corkum, P. ABCs of SLEEPING tool: Improving access to care for pediatric insomnia. Clin. Pract. Pediatr. Psychol. 2020, 8, 1–12. [Google Scholar] [CrossRef]
- Goodday, A.; Corkum, P.; Smith, I.M. Parental Acceptance of Treatments for Insomnia in Children with Attention-Deficit/Hyperactivity Disorder, Autistic Spectrum Disorder, and their Typically Developing Peers. Child. Health Care 2014, 43, 54–71. [Google Scholar] [CrossRef]
- Heussler, H.; Chan, P.; Price, A.M.H.; Waters, K.; Davey, M.J.; Hiscock, H. Pharmacological and non-pharmacological management of sleep disturbance in children: An Australian Paediatric Research Network survey. Sleep Med. 2013, 14, 189–194. [Google Scholar] [CrossRef] [PubMed]
- Whitehouse, A.J.O. Complementary and alternative medicine for autism spectrum disorders: Rationale, safety and efficacy. J. Paediatr. Child. Health 2013, 49, E438–E442. [Google Scholar] [CrossRef] [PubMed]
- Brondino, N.; Fusar-Poli, L.; Rocchetti, M.; Provenzani, U.; Barale, F.; Politi, P. Complementary and Alternative Therapies for Autism Spectrum Disorder. Evid. Based Complement. Alternat. Med. 2015, 2015, 258589. [Google Scholar] [CrossRef] [Green Version]
- Wang, C.; Preisser, J.; Chung, Y.; Li, K. Complementary and alternative medicine use among children with mental health issues: Results from the National Health Interview Survey. BMC Complement. Altern. Med. 2018, 18, 241. [Google Scholar] [CrossRef]
- Keogh, S.; Bridle, C.; Siriwardena, N.A.; Nadkarni, A.; Laparidou, D.; Durrant, S.J.; Kargas, N.; Law, G.R.; Curtis, F. Effectiveness of non-pharmacological interventions for insomnia in children with Autism Spectrum Disorder: A systematic review and meta-analysis. PLoS ONE 2019, 14, e0221428. [Google Scholar] [CrossRef]
- Williams Buckley, A.; Hirtz, D.; Oskoui, M.; Armstrong, M.J.; Batra, A.; Bridgemohan, C.; Coury, D.; Dawson, G.; Donley, D.; Findling, R.L.; et al. Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2020, 94, 392–404. [Google Scholar] [CrossRef] [Green Version]
- Bruni, O.; Angriman, M.; Melegari, M.G.; Ferri, R. Pharmacotherapeutic management of sleep disorders in children with neurodevelopmental disorders. Expert Opin. Pharmacother. 2019, 20, 2257–2271. [Google Scholar] [CrossRef]
- Relia, S.; Ekambaram, V. Pharmacological Approach to Sleep Disturbances in Autism Spectrum Disorders with Psychiatric Comorbidities: A Literature Review. Med. Sci. 2018, 6, 95. [Google Scholar] [CrossRef] [Green Version]
- Blackmer, A.B.; Feinstein, J.A. Management of Sleep Disorders in Children with Neurodevelopmental Disorders: A Review. Pharmacotherapy 2016, 36, 84–98. [Google Scholar] [CrossRef]
- Malow, B.; MacDonald, L.; Fawkes, D.; Alder, M.; Katz, T. Teaching Children with Autism Spectrum Disorder How to Sleep Better: A Pilot Educational Program for Parents. Clin. Pract. Pediatr. Psychol. 2016, 4. [Google Scholar] [CrossRef]
- Carnett, A.; Hansen, S.; McLay, L.; Neely, L.; Lang, R. Quantitative-Analysis of Behavioral Interventions to Treat Sleep Problems in Children with Autism. Dev. Neurorehabil. 2019, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Jan, J.E.; Owens, J.A.; Weiss, M.D.; Johnson, K.P.; Wasdell, M.B.; Freeman, R.D.; Ipsiroglu, O.S. Sleep hygiene for children with neurodevelopmental disabilities. Pediatrics 2008, 122, 1343–1350. [Google Scholar] [CrossRef] [PubMed]
- Honaker, S.M.; Meltzer, L.J. Bedtime Problems and Night Awakenings in Young Children: An Update of the Evidence. Paediatr. Respir. Rev. 2014, 15, 333–339. [Google Scholar] [CrossRef]
- Bruni, O.; Angriman, M.; Calisti, F.; Comandini, A.; Esposito, G.; Cortese, S.; Ferri, R. Practitioner Review: Treatment of chronic insomnia in children and adolescents with neurodevelopmental disabilities. J. Child. Psychol. Psychiatry 2018, 59, 489–508. [Google Scholar] [CrossRef]
- Adkins, K.W.; Molloy, C.; Weiss, S.K.; Reynolds, A.; Goldman, S.E.; Burnette, C.; Clemons, T.; Fawkes, D.; Malow, B.A. Effects of a standardized pamphlet on insomnia in children with autism spectrum disorders. Pediatrics 2012, 130 (Suppl. 2), S139–S144. [Google Scholar] [CrossRef] [Green Version]
- Malow, B.A.; Adkins, K.W.; Reynolds, A.; Weiss, S.K.; Loh, A.; Fawkes, D.; Katz, T.; Goldman, S.E.; Madduri, N.; Hundley, R.; et al. Parent-based sleep education for children with autism spectrum disorders. J. Autism Dev. Disord. 2014, 44, 216–228. [Google Scholar] [CrossRef] [Green Version]
- Johnson, C.R.; Turner, K.S.; Foldes, E.; Brooks, M.M.; Kronk, R.; Wiggs, L. Behavioral parent training to address sleep disturbances in young children with autism spectrum disorder: A pilot trial. Sleep Med. 2013, 14, 995–1004. [Google Scholar] [CrossRef] [Green Version]
- Papadopoulos, N.; Sciberras, E.; Hiscock, H.; Williams, K.; McGillivray, J.; Mihalopoulos, C.; Engel, L.; Fuller-Tyszkiewicz, M.; Bellows, S.T.; Marks, D.; et al. Sleeping sound with autism spectrum disorder (ASD): Study protocol for an efficacy randomised controlled trial of a tailored brief behavioural sleep intervention for ASD. BMJ Open 2019, 9, e029767. [Google Scholar] [CrossRef] [Green Version]
- Cuomo, B.M.; Vaz, S.; Lee, E.A.L.; Thompson, C.; Rogerson, J.M.; Falkmer, T. Effectiveness of Sleep-Based Interventions for Children with Autism Spectrum Disorder: A Meta-Synthesis. Pharmacotherapy 2017, 37, 555–578. [Google Scholar] [CrossRef]
- Roberts, C.A.; Smith, K.C.; Sherman, A.K. Comparison of Online and Face-to-Face Parent Education for Children with Autism and Sleep Problems. J. Autism Dev. Disord. 2019, 49, 1410–1422. [Google Scholar] [CrossRef] [PubMed]
- Kirkpatrick, B.; Louw, J.S.; Leader, G. Efficacy of parent training incorporated in behavioral sleep interventions for children with autism spectrum disorder and/or intellectual disabilities: A systematic review. Sleep Med. 2019, 53, 141–152. [Google Scholar] [CrossRef] [PubMed]
- McLay, L.K.; France, K.G.; Knight, J.; Blampied, N.M.; Hastie, B. The effectiveness of function-based interventions to treat sleep problems, including unwanted co-sleeping, in children with autism. Behav. Interv. 2019, 34, 30–51. [Google Scholar]
- Allen, S.L.; Howlett, M.D.; Coulombe, J.A.; Corkum, P.V. ABCs of SLEEPING: A review of the evidence behind pediatric sleep practice recommendations. Sleep Med. Rev. 2016, 29, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Paruthi, S.; Brooks, L.J.; D’Ambrosio, C.; Hall, W.A.; Kotagal, S.; Lloyd, R.M.; Malow, B.A.; Maski, K.; Nichols, C.; Quan, S.F.; et al. Recommended Amount of Sleep for Pediatric Populations: A Consensus Statement of the American Academy of Sleep Medicine. J. Clin. Sleep Med. 2016, 12, 785–786. [Google Scholar] [CrossRef]
- Owens, J.A.; Mindell, J.A. Pediatric insomnia. Pediatr. Clin. N. Am. 2011, 58, 555–569. [Google Scholar] [CrossRef]
- Turner, K.S.; Johnson, C.R. Behavioral Interventions to Address Sleep Disturbances in Children with Autism Spectrum Disorders: A Review. Top. Early Child. Spec. Educ. 2013, 33, 144–152. [Google Scholar] [CrossRef]
- Weiskop, S.; Matthews, J.; Richdale, A. Treatment of sleep problems in a 5-year-old boy with autism using behavioural principles. Autism 2001, 5, 209–221. [Google Scholar] [CrossRef]
- Herrmann, S. Counting Sheep: Sleep Disorders in Children with Autism Spectrum Disorders. J. Pediatr Health Care 2016, 30, 143–154. [Google Scholar] [CrossRef]
- Vriend, J.L.; Corkum, P.V.; Moon, E.C.; Smith, I.M. Behavioral interventions for sleep problems in children with autism spectrum disorders: Current findings and future directions. J. Pediatr Psychol. 2011, 36, 1017–1029. [Google Scholar] [CrossRef] [Green Version]
- Weiskop, S.; Richdale, A.; Matthews, J. Behavioural treatment to reduce sleep problems in children with autism or fragile X syndrome. Dev. Med. Child. Neurol. 2005, 47, 94–104. [Google Scholar] [CrossRef] [PubMed]
- Rigney, G.; Ali, N.S.; Corkum, P.V.; Brown, C.A.; Constantin, E.; Godbout, R.; Hanlon-Dearman, A.; Ipsiroglu, O.; Reid, G.J.; Shea, S.; et al. A systematic review to explore the feasibility of a behavioural sleep intervention for insomnia in children with neurodevelopmental disorders: A transdiagnostic approach. Sleep Med. Rev. 2018, 41, 244–254. [Google Scholar] [CrossRef] [PubMed]
- Schreck, K.A. Behavioral treatments for sleep problems in autism: Empirically supported or just universally accepted? Behav. Interv. 2001, 16, 265–278. [Google Scholar] [CrossRef]
- Didden, R.; Curfs, L.M.; Sikkema, S.P.; de Moor, J. Functional assessment and treatment of sleeping problems with developmentally disabled children: Six case studies. J. Behav. Ther. Exp. Psychiatry 1998, 29, 85–97. [Google Scholar] [CrossRef]
- Curfs, L.M.; Didden, R.; Sikkema, S.P.; De Die-Smulders, C.E. Management of sleeping problems in Wolf-Hirschhorn syndrome: A case study. Genet. Couns. 1999, 10, 345–350. [Google Scholar] [PubMed]
- Bramble, D. Rapid-acting treatment for a common sleep problem. Dev. Med. Child. Neurol. 1997, 39, 543–547. [Google Scholar]
- Allen, K.D.; Kuhn, B.R.; DeHaai, K.A.; Wallace, D.P. Evaluation of a behavioral treatment package to reduce sleep problems in children with Angelman Syndrome. Res. Dev. Disabil. 2013, 34, 676–686. [Google Scholar] [CrossRef]
- Kodak, T.; Piazza, C.C. Assessment and behavioral treatment of feeding and sleeping disorders in children with autism spectrum disorders. Child. Adolesc. Psychiatr. Clin. N. Am. 2008, 17, 887–905. [Google Scholar] [CrossRef]
- Van Deurs, J.R.; McLay, L.K.; France, K.G.; Blampied, N.M.; Lang, R.B.; Hunter, J.E. Behavioral Sleep Intervention for Adolescents with Autism Spectrum Disorder: A Pilot Study. Adv. Neurodev. Disord. 2019, 3, 397–410. [Google Scholar] [CrossRef]
- National Autism Center. National Standards Report—Addressing the Need for Evidence-Based Practice Guidelines for Autism Spectrum Disorders; National Autism Center: Randolph, MA, USA, 2009; pp. 1–3. [Google Scholar]
- Wiggs, L.; France, K. Behavioural treatments for sleep problems in children and adolescents with physical illness, psychological problems or intellectual disabilities. Sleep Med. Rev. 2000, 4, 299–314. [Google Scholar] [CrossRef]
- Angriman, M.; Caravale, B.; Novelli, L.; Ferri, R.; Bruni, O. Sleep in children with neurodevelopmental disabilities. Neuropediatrics 2015, 46, 199–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Creasey, N.; Finlay, F. Question 2: Do weighted blankets improve sleep in children with an autistic spectrum disorder? Arch. Dis. Child. 2013, 98, 919–920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McLay, L.-L.K.; France, K. Empirical research evaluating non-traditional approaches to managing sleep problems in children with autism. Dev. Neurorehabil. 2016, 19, 123–134. [Google Scholar] [CrossRef] [PubMed]
- Gringras, P.; Green, D.; Wright, B.; Rush, C.; Sparrowhawk, M.; Pratt, K.; Allgar, V.; Hooke, N.; Moore, D.; Zaiwalla, Z.; et al. Weighted blankets and sleep in autistic children--a randomized controlled trial. Pediatrics 2014, 134, 298–306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Frazier, T.W.; Krishna, J.; Klingemier, E.; Beukemann, M.; Nawabit, R.; Ibrahim, S. A Randomized, Crossover Trial of a Novel Sound-to-Sleep Mattress Technology in Children with Autism and Sleep Difficulties. J. Clin. Sleep Med. 2017, 13, 95–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Escalona, A.; Field, T.; Singer-Strunck, R.; Cullen, C.; Hartshorn, K. Brief report: Improvements in the behavior of children with autism following massage therapy. J. Autism Dev. Disord. 2001, 31, 513–516. [Google Scholar] [CrossRef]
- Silva, L.M.T.; Cignolini, A.; Warren, R.; Budden, S.; Skowron-Gooch, A. Improvement in sensory impairment and social interaction in young children with autism following treatment with an original Qigong massage methodology. Am. J. Chin. Med. 2007, 35, 393–406. [Google Scholar] [CrossRef]
- Piravej, K.; Tangtrongchitr, P.; Chandarasiri, P.; Paothong, L.; Sukprasong, S. Effects of Thai traditional massage on autistic children’s behavior. J. Altern. Complement. Med. 2009, 15, 1355–1361. [Google Scholar] [CrossRef]
- Silva, L.M.T.; Schalock, M.; Ayres, R.; Bunse, C.; Budden, S. Qigong massage treatment for sensory and self-regulation problems in young children with autism: A randomized controlled trial. Am. J. Occup. Ther. 2009, 63, 423–432. [Google Scholar] [CrossRef] [Green Version]
- Williams, T.I. Evaluating Effects of Aromatherapy Massage on Sleep in Children with Autism: A Pilot Study. Evid. Based Complement. Altern. Med. 2006, 3, 373–377. [Google Scholar] [CrossRef]
- Narasingharao, K.; Pradhan, B.; Navaneetham, J. Efficacy of Structured Yoga Intervention for Sleep, Gastrointestinal and Behaviour Problems of ASD Children: An Exploratory Study. J. Clin. Diagn. Res. 2017, 11, VC01–VC06. [Google Scholar] [CrossRef] [PubMed]
- Wachob, D.; Lorenzi, D.G. Brief Report: Influence of Physical Activity on Sleep Quality in Children with Autism. J. Autism Dev. Disord. 2015, 45, 2641–2646. [Google Scholar] [CrossRef] [PubMed]
- Tse, C.Y.A.; Lee, H.P.; Chan, K.S.K.; Edgar, V.B.; Wilkinson-Smith, A.; Lai, W.H.E. Examining the impact of physical activity on sleep quality and executive functions in children with autism spectrum disorder: A randomized controlled trial. Autism 2019, 23, 1699–1710. [Google Scholar] [CrossRef] [PubMed]
- Brand, S.; Jossen, S.; Holsboer-Trachsler, E.; Pühse, U.; Gerber, M. Impact of aerobic exercise on sleep and motor skills in children with autism spectrum disorders—A pilot study. Neuropsychiatr. Dis. Treat. 2015, 11, 1911–1920. [Google Scholar] [CrossRef] [Green Version]
- Oriel, K.N.; Kanupka, J.W.; DeLong, K.S.; Noel, K. The Impact of Aquatic Exercise on Sleep Behaviors in Children With Autism Spectrum Disorder: A Pilot Study. Focus Autism Dev. Disabil. 2016, 31, 254–261. [Google Scholar] [CrossRef]
- Lawson, L.M.; Little, L. Feasibility of a Swimming Intervention to Improve Sleep Behaviors of Children with Autism Spectrum Disorder. Ther. Recreat. J. 2017, 51. [Google Scholar] [CrossRef]
- Pelayo, R.; Yuen, K. Pediatric sleep pharmacology. Child. Adolesc. Psychiatr. Clin. N. Am. 2012, 21, 861–883. [Google Scholar] [CrossRef]
- Owens, J.A.; Rosen, C.L.; Mindell, J.A. Medication use in the treatment of pediatric insomnia: Results of a survey of community-based pediatricians. Pediatrics 2003, 111, e628–e635. [Google Scholar] [CrossRef] [Green Version]
- Kennaway, D.J. Melatonin and development: Physiology and pharmacology. Semin. Perinatol. 2000, 24, 258–266. [Google Scholar] [CrossRef]
- Bruni, O.; Alonso-Alconada, D.; Besag, F.; Biran, V.; Braam, W.; Cortese, S.; Moavero, R.; Parisi, P.; Smits, M.; Van der Heijden, K.; et al. Current role of melatonin in pediatric neurology: Clinical recommendations. Eur. J. Paediatr. Neurol. 2015, 19, 122–133. [Google Scholar] [CrossRef]
- Gobbi, G.; Comai, S. Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep. Front. Endocrinol. 2019, 10, 87. [Google Scholar] [CrossRef] [Green Version]
- Owens, J.A.; Rosen, C.L.; Mindell, J.A.; Kirchner, H.L. Use of pharmacotherapy for insomnia in child psychiatry practice: A national survey. Sleep Med. 2010, 11, 692–700. [Google Scholar] [CrossRef] [PubMed]
- Hartz, I.; Furu, K.; Bratlid, T.; Handal, M.; Skurtveit, S. Hypnotic drug use among 0–17 year olds during 2004–2011: A nationwide prescription database study. Scand. J. Public Health 2012, 40, 704–711. [Google Scholar] [CrossRef] [PubMed]
- Cortese, S.; Wang, F.; Angriman, M.; Masi, G.; Bruni, O. Sleep Disorders in Children and Adolescents with Autism Spectrum Disorder: Diagnosis, Epidemiology, and Management. CNS Drugs 2020, 34, 415–423. [Google Scholar] [CrossRef]
- Gringras, P.; Gamble, C.; Jones, A.P.; Wiggs, L.; Williamson, P.R.; Sutcliffe, A.; Montgomery, P.; Whitehouse, W.P.; Choonara, I.; Allport, T.; et al. Melatonin for sleep problems in children with neurodevelopmental disorders: Randomised double masked placebo controlled trial. BMJ 2012, 345, e6664. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Andersen, I.M.; Kaczmarska, J.; McGrew, S.G.; Malow, B.A. Melatonin for insomnia in children with autism spectrum disorders. J. Child. Neurol. 2008, 23, 482–485. [Google Scholar] [CrossRef] [PubMed]
- Wasdell, M.B.; Jan, J.E.; Bomben, M.M.; Freeman, R.D.; Rietveld, W.J.; Tai, J.; Hamilton, D.; Weiss, M.D. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J. Pineal Res. 2008, 44, 57–64. [Google Scholar] [CrossRef]
- Wirz-Justice, A.; Armstrong, S.M. Melatonin: Nature’s soporific? J. Sleep Res. 1996, 5, 137–141. [Google Scholar]
- Van Geijlswijk, I.M.; Korzilius, H.P.L.M.; Smits, M.G. The use of exogenous melatonin in delayed sleep phase disorder: A meta-analysis. Sleep 2010, 33, 1605–1614. [Google Scholar] [CrossRef]
- Burgess, H.J.; Revell, V.L.; Molina, T.A.; Eastman, C.I. Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. J. Clin. Endocrinol. Metab. 2010, 95, 3325–3331. [Google Scholar] [CrossRef] [Green Version]
- Keijzer, H.; Smits, M.G.; Peeters, T.; Looman, C.W.N.; Endenburg, S.C.; Gunnewiek, J.M.T.K. Evaluation of salivary melatonin measurements for Dim Light Melatonin Onset calculations in patients with possible sleep-wake rhythm disorders. Clin. Chim. Acta 2011, 412, 1616–1620. [Google Scholar] [CrossRef] [PubMed]
- Harrington, R.A.; Lee, L.-C.; Crum, R.M.; Zimmerman, A.W.; Hertz-Picciotto, I. Serotonin hypothesis of autism: Implications for selective serotonin reuptake inhibitor use during pregnancy. Autism Res. 2013, 6, 149–168. [Google Scholar] [CrossRef] [PubMed]
- Daly, E.; Ecker, C.; Hallahan, B.; Deeley, Q.; Craig, M.; Murphy, C.; Johnston, P.; Spain, D.; Gillan, N.; Gudbrandsen, M.; et al. Response inhibition and serotonin in autism: A functional MRI study using acute tryptophan depletion. Brain 2014, 137, 2600–2610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tordjman, S.; Anderson, G.M.; Pichard, N.; Charbuy, H.; Touitou, Y. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biol. Psychiatry 2005, 57, 134–138. [Google Scholar] [CrossRef] [PubMed]
- Goldman, S.E.; Adkins, K.W.; Calcutt, M.W.; Carter, M.D.; Goodpaster, R.L.; Wang, L.; Shi, Y.; Burgess, H.J.; Hachey, D.L.; Malow, B.A. Melatonin in children with autism spectrum disorders: Endogenous and pharmacokinetic profiles in relation to sleep. J. Autism Dev. Disord. 2014, 44, 2525–2535. [Google Scholar] [CrossRef] [Green Version]
- Melke, J.; Goubran Botros, H.; Chaste, P.; Betancur, C.; Nygren, G.; Anckarsäter, H.; Rastam, M.; Ståhlberg, O.; Gillberg, I.C.; Delorme, R.; et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol. Psychiatry 2008, 13, 90–98. [Google Scholar] [CrossRef] [Green Version]
- Rossignol, D.A.; Frye, R.E. Melatonin in autism spectrum disorders: A systematic review and meta-analysis. Dev. Med. Child. Neurol. 2011, 53, 783–792. [Google Scholar] [CrossRef]
- Veatch, O.J.; Pendergast, J.S.; Allen, M.J.; Leu, R.M.; Johnson, C.H.; Elsea, S.H.; Malow, B.A. Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay. J. Autism Dev. Disord. 2015, 45, 100–110. [Google Scholar] [CrossRef] [Green Version]
- Malow, B.A.; Byars, K.; Johnson, K.; Weiss, S.; Bernal, P.; Goldman, S.E.; Panzer, R.; Coury, D.L.; Glaze, D.G. Sleep Committee of the Autism Treatment Network A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents with autism spectrum disorders. Pediatrics 2012, 130 (Suppl. 2), S106–S124. [Google Scholar] [CrossRef] [Green Version]
- Hollway, J.A.; Aman, M.G. Pharmacological treatment of sleep disturbance in developmental disabilities: A review of the literature. Res. Dev. Disabil. 2011, 32, 939–962. [Google Scholar] [CrossRef]
- Guénolé, F.; Godbout, R.; Nicolas, A.; Franco, P.; Claustrat, B.; Baleyte, J.-M. Melatonin for disordered sleep in individuals with autism spectrum disorders: Systematic review and discussion. Sleep Med. Rev. 2011, 15, 379–387. [Google Scholar] [CrossRef] [PubMed]
- Sung, M.; Fung, D.S.S.; Cai, Y.; Ooi, Y.P. Pharmacological management in children and adolescents with pervasive developmental disorder. Aust. N. Z. J. Psychiatry 2010, 44, 410–428. [Google Scholar] [CrossRef] [PubMed]
- Cortesi, F.; Giannotti, F.; Sebastiani, T.; Panunzi, S.; Valente, D. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: A randomized placebo-controlled trial. J. Sleep Res. 2012, 21, 700–709. [Google Scholar] [CrossRef] [PubMed]
- Braam, W.; Keijzer, H.; Struijker Boudier, H.; Didden, R.; Smits, M.; Curfs, L. CYP1A2 polymorphisms in slow melatonin metabolisers: A possible relationship with autism spectrum disorder? J. Intellect. Disabil. Res. 2013, 57, 993–1000. [Google Scholar] [CrossRef]
- Braam, W.; van Geijlswijk, I.; Keijzer, H.; Smits, M.G.; Didden, R.; Curfs, L.M.G. Loss of response to melatonin treatment is associated with slow melatonin metabolism. J. Intellect. Disabil. Res. 2010, 54, 547–555. [Google Scholar] [CrossRef]
- Gringras, P.; Nir, T.; Breddy, J.; Frydman-Marom, A.; Findling, R.L. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J. Am. Acad. Child. Adolesc. Psychiatry 2017, 56, 948–957.e4. [Google Scholar] [CrossRef] [Green Version]
- Schroder, C.M.; Malow, B.A.; Maras, A.; Melmed, R.D.; Findling, R.L.; Breddy, J.; Nir, T.; Shahmoon, S.; Zisapel, N.; Gringras, P. Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver’s Quality of Life. J. Autism Dev. Disord. 2019, 49, 3218–3230. [Google Scholar] [CrossRef] [Green Version]
- Maras, A.; Schroder, C.M.; Malow, B.A.; Findling, R.L.; Breddy, J.; Nir, T.; Shahmoon, S.; Zisapel, N.; Gringras, P. Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J. Child. Adolesc. Psychopharmacol. 2018, 28, 699–710. [Google Scholar] [CrossRef]
- Malow, B.A.; Findling, R.L.; Schroder, C.M.; Maras, A.; Breddy, J.; Nir, T.; Zisapel, N.; Gringras, P. Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children with Autism Spectrum Disorder. J. Am. Acad. Child. Adolesc. Psychiatry 2020. [Google Scholar] [CrossRef] [Green Version]
- Brown, R.E.; Stevens, D.R.; Haas, H.L. The physiology of brain histamine. Prog. Neurobiol. 2001, 63, 637–672. [Google Scholar] [CrossRef]
- Eriksson, K.S.; Sergeeva, O.; Brown, R.E.; Haas, H.L. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J. Neurosci. 2001, 21, 9273–9279. [Google Scholar] [CrossRef] [PubMed]
- Stahl, S.M. Selective histamine H1 antagonism: Novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008, 13, 1027–1038. [Google Scholar] [CrossRef] [Green Version]
- Thakkar, M.M. Histamine in the regulation of wakefulness. Sleep Med. Rev. 2011, 15, 65–74. [Google Scholar] [CrossRef] [Green Version]
- Shirley, D.W.; Sterrett, J.; Haga, N.; Durham, C. The therapeutic versatility of antihistamines: A comprehensive review. Nurse Pract. 2020, 45, 8–21. [Google Scholar] [CrossRef] [PubMed]
- Fitzsimons, R.; Van der Poel, L.-A.; Thornhill, W.; Du Toit, G.; Shah, N.; Brough, H.A. Antihistamine use in children. Arch. Dis. Child. Educ. Pract. Ed. 2015, 100, 122–131. [Google Scholar] [CrossRef] [Green Version]
- Simons, F.E.R.; Simons, K.J. H1 antihistamines: Current status and future directions. World Allergy Organ. J. 2008, 1, 145–155. [Google Scholar] [CrossRef] [PubMed]
- Schnoes, C.J.; Kuhn, B.R.; Workman, E.F.; Ellis, C.R. Pediatric prescribing practices for clonidine and other pharmacologic agents for children with sleep disturbance. Clin. Pediatr. 2006, 45, 229–238. [Google Scholar] [CrossRef] [PubMed]
- Church, M.K.; Maurer, M.; Simons, F.E.R.; Bindslev-Jensen, C.; Van Cauwenberge, P.; Bousquet, J.; Holgate, S.T.; Zuberbier, T. Global Allergy and Asthma European Network Risk of first-generation H(1)-antihistamines: A GA(2)LEN position paper. Allergy 2010, 65, 459–466. [Google Scholar] [CrossRef] [PubMed]
- Kalpaklioglu, F.; Baccioglu, A. Efficacy and safety of H1-antihistamines: An update. Antiinflamm. Antiallergy Agents Med. Chem. 2012, 11, 230–237. [Google Scholar] [CrossRef]
- Russo, R.M.; Gururaj, V.J.; Allen, J.E. The effectiveness of diphenhydramine HCl in pediatric sleep disorders. J. Clin. Pharmacol. 1976, 16, 284–288. [Google Scholar] [CrossRef]
- Merenstein, D.; Diener-West, M.; Halbower, A.C.; Krist, A.; Rubin, H.R. The Trial of Infant Response to Diphenhydramine: The TIRED Study—A Randomized, Controlled, Patient-Oriented Trial. Arch. Pediatr. Adolesc. Med. 2006, 160, 707–712. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sezer, T.; Alehan, F. Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording. Int. J. Neurosci. 2013, 123, 719–723. [Google Scholar] [CrossRef] [PubMed]
- Montanari, G.; Schiaulini, P.; Covre, A.; Steffan, A.; Furlanut, M. Niaprazine vs. chlordesmethyldiazepam in sleep disturbances in pediatric outpatients. Pharmacol. Res. 1992, 25 (Suppl. 1), 83–84. [Google Scholar] [CrossRef]
- Ottaviano, S.; Giannotti, F.; Cortesi, F. The effect of niaprazine on some common sleep disorders in children. A double-blind clinical trial by means of continuous home-videorecorded sleep. Child. Nerv. Syst. 1991, 7, 332–335. [Google Scholar] [CrossRef] [PubMed]
- Teutsch, G.; Mahler, D.L.; Brown, C.R.; Forrest, W.H.; James, K.E.; Brown, B.W. Hypnotic efficacy of diphenhydramine, methapyrilene, and pentobarbital. Clin. Pharmacol. Ther. 1975, 17, 195–201. [Google Scholar] [CrossRef] [PubMed]
- France, K.G.; Blampied, N.M.; Wilkinson, P. A multiple-baseline, double-blind evaluation of the effects of trimeprazine tartrate on infant sleep disturbance. Exp. Clin. Psychopharmacol. 1999, 7, 502–513. [Google Scholar] [CrossRef]
- Gringras, P. When to use drugs to help sleep. Arch. Dis. Child. 2008, 93, 976–981. [Google Scholar] [CrossRef]
- Vuurman, E.F.; Van Veggel, L.M.; Uiterwijk, M.M.; Leutner, D.; O’Hanlon, J.F. Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann. Allergy 1993, 71, 121–126. [Google Scholar] [CrossRef]
- Dinndorf, P.A.; McCabe, M.A.; Frierdich, S. Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses. J. Pediatr. 1998, 133, 293–295. [Google Scholar] [CrossRef]
- Sutter, A.I.M.; Lemiengre, M.; Campbell, H.; Mackinnon, H.F. Antihistamines for the common cold. Cochrane Database Syst. Rev. 2003, CD001267. [Google Scholar] [CrossRef] [Green Version]
- Magera, B.E.; Betlach, C.J.; Sweatt, A.P.; Derrick, C.W. Hydroxyzine intoxication in a 13-month-old child. Pediatrics 1981, 67, 280–283. [Google Scholar] [PubMed]
- Anagnostou, K.; Swan, K.; Brough, H. The use of antihistamines in children. Paediatr. Child. Health 2016. [Google Scholar] [CrossRef]
- Friedman, M. Analysis, Nutrition, and Health Benefits of Tryptophan. Int. J. Tryptophan Res. 2018, 11, 1178646918802282. [Google Scholar] [CrossRef] [Green Version]
- Meolie, A.L.; Rosen, C.; Kristo, D.; Kohrman, M.; Gooneratne, N.; Aguillard, R.N.; Fayle, R.; Troell, R.; Townsend, D.; Claman, D.; et al. Oral nonprescription treatment for insomnia: An evaluation of products with limited evidence. J. Clin. Sleep Med. 2005, 1, 173–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Monti, J.M. Serotonin control of sleep-wake behavior. Sleep Med. Rev. 2011, 15, 269–281. [Google Scholar] [CrossRef]
- Imeri, L.; Mancia, M.; Bianchi, S.; Opp, M.R. 5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in rats. Neuroscience 2000, 95, 445–452. [Google Scholar] [CrossRef]
- Hartmann, E.; Spinweber, C.L. Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake. J. Nerv. Ment. Dis. 1979, 167, 497–499. [Google Scholar] [CrossRef]
- Schneider-Helmert, D.; Spinweber, C.L. Evaluation of L-tryptophan for treatment of insomnia: A review. Psychopharmacology 1986, 89, 1–7. [Google Scholar] [CrossRef]
- Spinweber, C.L. L-tryptophan administered to chronic sleep-onset insomniacs: Late-appearing reduction of sleep latency. Psychopharmacology 1986, 90, 151–155. [Google Scholar] [CrossRef]
- Hartmann, E. Editorial: L-tryptophan: A possible natural hypnotic substance. JAMA 1974, 230, 1680–1681. [Google Scholar] [CrossRef]
- Bergonzi, P.; Capocchi, G.; Chiurulla, C.; Mennuni, G.; Tempesta, E. Tryptophan and sleep in subjects with neuropsychiatric syndromes. Riv. Neurol. 1973, 43, 403–409. [Google Scholar] [PubMed]
- Lieberman, H.R.; Agarwal, S.; Fulgoni, V.L. Tryptophan Intake in the US Adult Population Is Not Related to Liver or Kidney Function but Is Associated with Depression and Sleep Outcomes. J. Nutr. 2016, 146, 2609S–2615S. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wyatt, R.J.; Zarcone, V.; Engelman, K.; Dement, W.C.; Snyder, F.; Sjoerdsma, A. Effects of 5-hydroxytryptophan on the sleep of normal human subjects. Electroencephalogr. Clin. Neurophysiol. 1971, 30, 505–509. [Google Scholar] [CrossRef]
- Birdsall, T.C. 5-Hydroxytryptophan: A clinically-effective serotonin precursor. Altern. Med. Rev. 1998, 3, 271–280. [Google Scholar]
- Fernstrom, J.D. Effects and side effects associated with the non-nutritional use of tryptophan by humans. J. Nutr. 2012, 142, 2236S–2244S. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Das, Y.T.; Bagchi, M.; Bagchi, D.; Preuss, H.G. Safety of 5-hydroxy-L-tryptophan. Toxicol. Lett. 2004, 150, 111–122. [Google Scholar] [CrossRef]
- Bruni, O.; Ferri, R.; Miano, S.; Verrillo, E. L -5-Hydroxytryptophan treatment of sleep terrors in children. Eur. J. Pediatr. 2004, 163, 402–407. [Google Scholar] [CrossRef]
- Van Zyl, L.T.; Chung, S.A.; Shahid, A.; Shapiro, C.M. L-Tryptophan as Treatment for Pediatric Non-Rapid Eye Movement Parasomnia. J. Child. Adolesc. Psychopharmacol. 2018, 28, 395–401. [Google Scholar] [CrossRef]
- Bravaccio, C.; Terrone, G.; Rizzo, R.; Gulisano, M.; Tosi, M.; Curatolo, P.; Emberti Gialloreti, L. Use of nutritional supplements based on melatonin, tryptophan and vitamin B6 (Melamil Tripto®) in children with primary chronic headache, with or without sleep disorders: A pilot study. Minerva Pediatr. 2020, 72, 30–36. [Google Scholar] [CrossRef]
- Della Volpe, A.; Lucia, A.D.; Pirozzi, C.; Pastore, V. Comparative Study between the use of Melatonin and A Solution with Melatonin, Tryptophan, and Vitamin B6 as an Inducer of Spontaneous Sleep in Children During an Auditory Response Test: An Alternative to Commonly Used Sedative Drugs. J. Int. Adv. Otol. 2017, 13, 69–73. [Google Scholar] [CrossRef]
- Harada, T.; Hirotani, M.; Maeda, M.; Nomura, H.; Takeuchi, H. Correlation between breakfast tryptophan content and morning-evening in Japanese infants and students aged 0–15 yrs. J. Physiol. Anthropol. 2007, 26, 201–207. [Google Scholar] [CrossRef] [Green Version]
- Cubero, J.; Chanclón, B.; Sánchez, S.; Rivero, M.; Rodríguez, A.B.; Barriga, C. Improving the quality of infant sleep through the inclusion at supper of cereals enriched with tryptophan, adenosine-5’-phosphate, and uridine-5’-phosphate. Nutr. Neurosci. 2009, 12, 272–280. [Google Scholar] [CrossRef] [PubMed]
- Yap, I.K.S.; Angley, M.; Veselkov, K.A.; Holmes, E.; Lindon, J.C.; Nicholson, J.K. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J. Proteome Res. 2010, 9, 2996–3004. [Google Scholar] [CrossRef] [Green Version]
- Boccuto, L.; Chen, C.-F.; Pittman, A.R.; Skinner, C.D.; McCartney, H.J.; Jones, K.; Bochner, B.R.; Stevenson, R.E.; Schwartz, C.E. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol. Autism 2013, 4, 16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gevi, F.; Zolla, L.; Gabriele, S.; Persico, A.M. Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism. Mol. Autism 2016, 7, 47. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guiotto, A.; Calderan, A.; Ruzza, P.; Borin, G. Carnosine and carnosine-related antioxidants: A review. Curr. Med. Chem. 2005, 12, 2293–2315. [Google Scholar] [CrossRef] [PubMed]
- Ming, X.; Stein, T.P.; Barnes, V.; Rhodes, N.; Guo, L. Metabolic perturbance in autism spectrum disorders: A metabolomics study. J. Proteome Res. 2012, 11, 5856–5862. [Google Scholar] [CrossRef]
- Bala, K.A.; Doğan, M.; Mutluer, T.; Kaba, S.; Aslan, O.; Balahoroğlu, R.; Çokluk, E.; Üstyol, L.; Kocaman, S. Plasma amino acid profile in autism spectrum disorder (ASD). Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 923–929. [Google Scholar]
- Villafuerte, G.; Miguel-Puga, A.; Rodríguez, E.M.; Machado, S.; Manjarrez, E.; Arias-Carrión, O. Sleep deprivation and oxidative stress in animal models: A systematic review. Oxid. Med. Cell Longev. 2015, 2015, 234952. [Google Scholar] [CrossRef]
- Chez, M.G.; Buchanan, C.P.; Aimonovitch, M.C.; Becker, M.; Schaefer, K.; Black, C.; Komen, J. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J. Child. Neurol. 2002, 17, 833–837. [Google Scholar] [CrossRef]
- Mehrazad-Saber, Z.; Kheirouri, S.; Noorazar, S.-G. Effects of L-Carnosine Supplementation on Sleep Disorders and Disease Severity in Autistic Children: A Randomized, Controlled Clinical Trial. Basic Clin. Pharmacol. Toxicol. 2018, 123, 72–77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hare, D.J.; Ayton, S.; Bush, A.I.; Lei, P. A delicate balance: Iron metabolism and diseases of the brain. Front. Aging Neurosci. 2013, 5. [Google Scholar] [CrossRef] [Green Version]
- Marques, A.H.; O’Connor, T.G.; Roth, C.; Susser, E.; Bjørke-Monsen, A.-L. The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders. Front. Neurosci. 2013, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leung, W.; Singh, I.; McWilliams, S.; Stockler, S.; Ipsiroglu, O.S. Iron deficiency and sleep—A scoping review. Sleep Med. Rev. 2020, 51. [Google Scholar] [CrossRef] [PubMed]
- Earley, C.J.; Allen, R.P.; Beard, J.L.; Connor, J.R. Insight into the pathophysiology of restless legs syndrome. J. Neurosci. Res. 2000, 62, 623–628. [Google Scholar] [CrossRef]
- Sloand, J.A.; Shelly, M.A.; Feigin, A.; Bernstein, P.; Monk, R.D. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am. J. Kidney Dis. 2004, 43, 663–670. [Google Scholar] [CrossRef]
- Allen, R.P.; Adler, C.H.; Du, W.; Butcher, A.; Bregman, D.B.; Earley, C.J. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: A multi-centred, placebo-controlled preliminary clinical trial. Sleep Med. 2011, 12, 906–913. [Google Scholar] [CrossRef]
- Kotagal, S. Treatment of dyssomnias and parasomnias in childhood. Curr. Treat. Options Neurol. 2012, 14, 630–649. [Google Scholar] [CrossRef]
- Kerstein, R.; Stimpson, P.; Caulfield, H.; Ellis, G. Iron deficiency and sleep disordered breathing in children--cause or effect? Int. J. Pediatr. Otorhinolaryngol. 2009, 73, 275–280. [Google Scholar] [CrossRef]
- Konofal, E.; Lecendreux, M.; Deron, J.; Marchand, M.; Cortese, S.; Zaïm, M.; Mouren, M.C.; Arnulf, I. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr. Neurol. 2008, 38, 20–26. [Google Scholar] [CrossRef]
- DelRosso, L.M.; Bruni, O.; Ferri, R. Restless sleep disorder in children: A pilot study on a tentative new diagnostic category. Sleep 2018, 41. [Google Scholar] [CrossRef] [PubMed]
- Georgieff, M.K. Iron assessment to protect the developing brain. Am. J. Clin. Nutr. 2017, 106, 1588S–1593S. [Google Scholar] [CrossRef]
- Dosman, C.F.; Drmic, I.E.; Brian, J.A.; Senthilselvan, A.; Harford, M.; Smith, R.; Roberts, S.W. Ferritin as an indicator of suspected iron deficiency in children with autism spectrum disorder: Prevalence of low serum ferritin concentration. Dev. Med. Child. Neurol. 2006, 48, 1008–1009. [Google Scholar] [CrossRef] [PubMed]
- Gunes, S.; Ekinci, O.; Celik, T. Iron deficiency parameters in autism spectrum disorder: Clinical correlates and associated factors. Ital. J. Pediatr. 2017, 43, 86. [Google Scholar] [CrossRef] [PubMed]
- Clénin, G.E. The treatment of iron deficiency without anaemia (in otherwise healthy persons). Swiss Med. Wkly. 2017, 147, w14434. [Google Scholar] [CrossRef] [PubMed]
- DelRosso, L.M.; Chan, J.H.M.; Wrede, J.E.; Lockhart, C.T.; Yi, T.; Ferri, R. Determinants of ferritin response to oral iron supplementation in children with sleep movement disorders. Sleep 2020, 43. [Google Scholar] [CrossRef]
- Oatley, H.; Borkhoff, C.M.; Chen, S.; Macarthur, C.; Persaud, N.; Birken, C.S.; Maguire, J.L.; Parkin, P.C.; Targ, K. Screening for Iron Deficiency in Early Childhood Using Serum Ferritin in the Primary Care Setting. Pediatrics 2018, 142. [Google Scholar] [CrossRef] [Green Version]
- Panagiotou, J.P.; Douros, K. Clinicolaboratory Findings and Treatment of Iron-Deficiency Anemia in Childhood. Pediatr. Hematol. Oncol. 2004, 21, 519–532. [Google Scholar] [CrossRef]
- Lane, R.; Kessler, R.; Buckley, A.W.; Rodriguez, A.; Farmer, C.; Thurm, A.; Swedo, S.; Felt, B. Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children with Autism. Pediatr. Neurol. 2015, 53, 343–349. [Google Scholar] [CrossRef] [Green Version]
- Youssef, J.; Singh, K.; Huntington, N.; Becker, R.; Kothare, S.V. Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders. Pediatr. Neurol. 2013, 49, 274–278. [Google Scholar] [CrossRef]
- Dosman, C.F.; Brian, J.A.; Drmic, I.E.; Senthilselvan, A.; Harford, M.M.; Smith, R.W.; Sharieff, W.; Zlotkin, S.H.; Moldofsky, H.; Roberts, S.W. Children with autism: Effect of iron supplementation on sleep and ferritin. Pediatr. Neurol. 2007, 36, 152–158. [Google Scholar] [CrossRef] [PubMed]
- Munzer, T.; Felt, B. The Role of Iron in Pediatric Restless Legs Syndrome and Periodic Limb Movements in Sleep. Semin. Neurol. 2017, 37, 439–445. [Google Scholar] [CrossRef] [PubMed]
- Picchietti, D.L. Should oral iron be first-line therapy for pediatric restless legs syndrome and periodic limb movement disorder? Sleep Med. 2017, 32, 220–221. [Google Scholar] [CrossRef] [PubMed]
- DelRosso, L.; Bruni, O. Treatment of pediatric restless legs syndrome. In Advances in Pharmacology; Elsevier: Amsterdam, The Netherlands, 2019; Volume 84, pp. 237–253. ISBN 978-0-12-816758-8. [Google Scholar]
- Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281. [Google Scholar] [CrossRef] [PubMed]
- Muscogiuri, G.; Barrea, L.; Scannapieco, M.; Di Somma, C.; Scacchi, M.; Aimaretti, G.; Savastano, S.; Colao, A.; Marzullo, P. The lullaby of the sun: The role of vitamin D in sleep disturbance. Sleep Med. 2019, 54, 262–265. [Google Scholar] [CrossRef]
- Wali, S.; Alsafadi, S.; Abaalkhail, B.; Ramadan, I.; Abulhamail, B.; Kousa, M.; Alshamrani, R.; Faruqui, H.; Faruqui, A.; Alama, M.; et al. The Association Between Vitamin D Level and Restless Legs Syndrome: A Population-Based Case-Control Study. J. Clin. Sleep Med. 2018, 14, 557–564. [Google Scholar] [CrossRef]
- Lima, L.A.R.; Lopes, M.J.P.; Costa, R.O.; Lima, F.A.V.; Neves, K.R.T.; Calou, I.B.F.; Andrade, G.M.; Viana, G.S.B. Vitamin D protects dopaminergic neurons against neuroinflammation and oxidative stress in hemiparkinsonian rats. J. Neuroinflamm. 2018, 15, 249. [Google Scholar] [CrossRef]
- Nakamura, K.; Wang, W.; Kang, U.J. The Role of Glutathione in Dopaminergic Neuronal Survival. J. Neurochem. 1997, 69, 1850–1858. [Google Scholar] [CrossRef] [PubMed]
- Orme, R.P.; Bhangal, M.S.; Fricker, R.A. Calcitriol imparts neuroprotection in vitro to midbrain dopaminergic neurons by upregulating GDNF expression. PLoS ONE 2013, 8, e62040. [Google Scholar] [CrossRef] [Green Version]
- Jin, H.J.; Lee, J.H.; Kim, M.K. The prevalence of vitamin D deficiency in iron-deficient and normal children under the age of 24 months. Blood Res. 2013, 48, 40–45. [Google Scholar] [CrossRef] [Green Version]
- Yong, C.Y.; Reynaud, E.; Forhan, A.; Dargent-Molina, P.; Heude, B.; Charles, M.-A.; Plancoulaine, S.; Annesi-Maesano, I.; Bernard, J.Y.; Botton, J.; et al. Cord-blood vitamin D level and night sleep duration in preschoolers in the EDEN mother-child birth cohort. Sleep Med. 2019, 53, 70–74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Deng, Y.; Wang, G.; Ye, X.; Jiang, Y.; Lin, Q.; Dong, S.; Song, Y.; Zhu, L.; Meng, M.; Li, W.; et al. The association between 25-hydroxyvitamin D levels and children’s sleep-wake patterns: A prospective cohort study. Sleep Med. 2020, 67, 207–214. [Google Scholar] [CrossRef] [PubMed]
- Gong, Q.-H.; Li, S.-X.; Li, H.; Chen, Q.; Li, X.-Y.; Xu, G.-Z. 25-Hydroxyvitamin D Status and Its Association with Sleep Duration in Chinese Schoolchildren. Nutrients 2018, 10, 1013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, T.; Shan, L.; Du, L.; Feng, J.; Xu, Z.; Staal, W.G.; Jia, F. Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: A systematic review and meta-analysis. Eur. Child. Adolesc. Psychiatry 2016, 25, 341–350. [Google Scholar] [CrossRef]
- Bivona, G.; Gambino, C.M.; Iacolino, G.; Ciaccio, M. Vitamin D and the nervous system. Neurol. Res. 2019, 41, 827–835. [Google Scholar] [CrossRef]
- Bouillon, R. Comparative analysis of nutritional guidelines for vitamin D. Nat. Rev. Endocrinol. 2017, 13, 466–479. [Google Scholar] [CrossRef]
- Gominak, S.C.; Stumpf, W.E. The world epidemic of sleep disorders is linked to vitamin D deficiency. Med. Hypotheses 2012, 79, 132–135. [Google Scholar] [CrossRef]
- Adams, J.B.; Holloway, C. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J. Altern. Complement. Med. 2004, 10, 1033–1039. [Google Scholar] [CrossRef]
- Adams, J.B.; Audhya, T.; McDonough-Means, S.; Rubin, R.A.; Quig, D.; Geis, E.; Gehn, E.; Loresto, M.; Mitchell, J.; Atwood, S.; et al. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr. 2011, 11, 111. [Google Scholar] [CrossRef]
- Gyllenhaal, C.; Merritt, S.L.; Peterson, S.D.; Block, K.I.; Gochenour, T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med. Rev. 2000, 4, 229–251. [Google Scholar] [CrossRef]
- Guadagna, S.; Barattini, D.F.; Rosu, S.; Ferini-Strambi, L. Plant Extracts for Sleep Disturbances: A Systematic Review...Vitafoods 2019 in Geneva. Evid.-Based Complement. Altern. Med. 2020, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mineo, L.; Concerto, C.; Patel, D.; Mayorga, T.; Paula, M.; Chusid, E.; Aguglia, E.; Battaglia, F. Valeriana officinalis Root Extract Modulates Cortical Excitatory Circuits in Humans. Neuropsychobiology 2017, 75, 46–51. [Google Scholar] [CrossRef] [PubMed]
- Houghton, P.J. The scientific basis for the reputed activity of Valerian. J. Pharm. Pharmacol. 1999, 51, 505–512. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.E.; Schumacher, B.; Brattström, A.; Abourashed, E.A.; Koetter, U. Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors. Life Sci. 2002, 71, 1939–1949. [Google Scholar] [CrossRef]
- Leach, M.J.; Page, A.T. Herbal medicine for insomnia: A systematic review and meta-analysis. Sleep Med. Rev. 2015, 24, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Leathwood, P.D.; Chauffard, F.; Heck, E.; Munoz-Box, R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol. Biochem. Behav. 1982, 17, 65–71. [Google Scholar] [CrossRef]
- Herrera-Arellano, A.; Luna-Villegas, G.; Cuevas-Uriostegui, M.; Alvarez, L.; Vargas-Pineda, G.; Zamilpa, A.; Tortoriello, J. Polysomnographic Evaluation of the Hypnotic Effect of Valeriana edulis Standardized Extract in Patients Suffering from Insomnia. Planta Medica 2001, 67, 695–699. [Google Scholar] [CrossRef]
- Taavoni, S.; Nazem ekbatani, N.; Haghani, H. Valerian/lemon balm use for sleep disorders during menopause. Complement. Ther. Clin. Pract. 2013, 19, 193–196. [Google Scholar] [CrossRef]
- Oxman, A.D.; Flottorp, S.; Håvelsrud, K.; Fretheim, A.; Odgaard-Jensen, J.; Austvoll-Dahlgren, A.; Carling, C.; Pallesen, S.; Bjorvatn, B. A Televised, Web-Based Randomised Trial of an Herbal Remedy (Valerian) for Insomnia. PLoS ONE 2007, 2, e1040. [Google Scholar] [CrossRef]
- Cuellar, N.G.; Ratcliffe, S.J. Does valerian improve sleepiness and symptom severity in people with restless legs syndrome? Altern. Ther. Health Med. 2009, 15, 22–28. [Google Scholar]
- Barton, D.L.; Atherton, P.J.; Bauer, B.A.; Moore, D.F.; Mattar, B.I.; Lavasseur, B.I.; Rowland, K.M.; Zon, R.T.; Lelindqwister, N.A.; Nagargoje, G.G.; et al. The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: A phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5). J. Support. Oncol. 2011, 9, 24–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jacobs, B.P.; Bent, S.; Tice, J.A.; Blackwell, T.; Cummings, S.R. An Internet-Based Randomized, Placebo-Controlled Trial of Kava and Valerian for Anxiety and Insomnia. Medicine 2005, 84, 197–207. [Google Scholar] [CrossRef] [PubMed]
- Świąder, K.; Wijaya, C.H.; Startek, K. The therapeutic properties of Lemon balm (Melissa officinalis L.): Reviewing novel findings and medical indications. J. Appl. Bot. Food Qual. 2019, 92, 327–335. [Google Scholar] [CrossRef]
- Cerny, A.; Schmid, K. Tolerability and efficacy of valerian/lemon balm in healthy volunteers (a double-blind, placebo-controlled, multicentre study). Fitoterapia 1999, 70, 221–228. [Google Scholar] [CrossRef]
- Cases, J.; Ibarra, A.; Feuillère, N.; Roller, M.; Sukkar, S.G. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med. J. Nutr. Metab. 2011, 4, 211–218. [Google Scholar] [CrossRef] [Green Version]
- Müller, S.F.; Klement, S. A combination of valerian and lemon balm is effective in the treatment of restlessness and dyssomnia in children. Phytomedicine 2006, 13, 383–387. [Google Scholar] [CrossRef]
- Tavares-Silva, C.; Holandino, C.; Homsani, F.; Luiz, R.R.; Prodestino, J.; Farah, A.; De Lima, J.P.; Simas, R.C.; Castilho, C.V.V.; Leitão, S.G.; et al. Homeopathic medicine of Melissa officinalis combined or not with Phytolacca decandra in the treatment of possible sleep bruxism in children: A crossover randomized triple-blinded controlled clinical trial. Phytomedicine 2019, 58, 152869. [Google Scholar] [CrossRef]
- Dhawan, K.; Dhawan, S.; Sharma, A. Passiflora: A review update. J. Ethnopharmacol. 2004, 94, 1–23. [Google Scholar] [CrossRef]
- Toda, K.; Hitoe, S.; Takeda, S.; Shimizu, N.; Shimoda, H. Passionflower Extract Induces High-amplitude Rhythms without Phase Shifts in the Expression of Several Circadian Clock Genes in Vitro and in Vivo. Int. J. Biomed. Sci. 2017, 13, 84–92. [Google Scholar]
- Lee, J.; Jung, H.-Y.; Lee, S.I.; Choi, J.H.; Kim, S.-G. Effects of Passiflora incarnata Linnaeus on polysomnographic sleep parameters in subjects with insomnia disorder: A double-blind randomized placebo-controlled study. Int. Clin. Psychopharmacol. 2020, 35, 29–35. [Google Scholar] [CrossRef]
- Woelk, H.; Schläfke, S. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder. Phytomedicine 2010, 17, 94–99. [Google Scholar] [CrossRef] [PubMed]
- Kasper, S.; Gastpar, M.; Müller, W.E.; Volz, H.-P.; Möller, H.-J.; Dienel, A.; Schläfke, S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of “subsyndromal” anxiety disorder: A randomized, double-blind, placebo controlled trial. Int. Clin. Psychopharmacol. 2010, 25, 277–287. [Google Scholar] [CrossRef] [PubMed]
- Kasper, S.; Anghelescu, I.; Dienel, A. Efficacy of orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep--A randomized, placebo-controlled trial. Eur. Neuropsychopharmacol. 2015, 25, 1960–1967. [Google Scholar] [CrossRef] [PubMed]
- Uehleke, B.; Schaper, S.; Dienel, A.; Schlaefke, S.; Stange, R. Phase II trial on the effects of Silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder. Phytomed. Int. J. Phytother. Phytopharmacol. 2012, 19, 665–672. [Google Scholar] [CrossRef]
- Nathan, P. The experimental and clinical pharmacology of St John’s Wort (Hypericum perforatum L.). Mol. Psychiatry 1999, 4, 333–338. [Google Scholar] [CrossRef] [Green Version]
- Müller, W.E.; Singer, A.; Wonnemann, M.; Hafner, U.; Rolli, M.; Schäfer, C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry 1998, 31, 16–21. [Google Scholar] [CrossRef]
- Nathan, P.J. Hypericum perforatum (St John’s Wort): A non-selective reuptake inhibitor? A review of the recent advances in its pharmacology. J. Psychopharmacol. 2001, 15, 47–54. [Google Scholar] [CrossRef]
- Al-Akoum, M.; Maunsell, E.; Verreault, R.; Provencher, L.; Otis, H.; Dodin, S. Effects of Hypericum perforatum (St. John’s wort) on hot flashes and quality of life in perimenopausal women: A randomized pilot trial. Menopause 2009, 16, 307–314. [Google Scholar] [CrossRef]
- Sharpley, A.L.; McGavin, C.L.; Whale, R.; Cowen, P.J. Antidepressant-like effect of Hypericum perforatum (St John’s wort) on the sleep polysomnogram. Psychopharmacology 1998, 139, 286–287. [Google Scholar] [CrossRef]
- Adib-Hajbaghery, M.; Mousavi, S.N. The effects of chamomile extract on sleep quality among elderly people: A clinical trial. Complement. Ther. Med. 2017, 35, 109–114. [Google Scholar] [CrossRef]
- Chang, S.M.; Chen, C.-H. Effects of an intervention with drinking chamomile tea on sleep quality and depression in sleep disturbed postnatal women: A randomized controlled trial. J. Adv. Nurs. 2016, 72, 306–315. [Google Scholar] [CrossRef] [PubMed]
- Zick, S.M.; Wright, B.D.; Sen, A.; Arnedt, J.T. Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: A randomized placebo-controlled pilot study. BMC Complement. Altern. Med. 2011, 11, 78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Level 1 | Sleep education and implementation of healthy sleep practices |
Level 2 | Specific behavioral strategies |
Level 3 | Medications |
Practice Areas | Recommendations | Level of Empirical Support 1 |
---|---|---|
Age-appropriate Bedtime, wake-times, and naps with Consistency | - Consistency of bedtimes, wake-times, and naps | Strong |
- Bedtime no later than 9 p.m. | Moderate | |
- Age-appropriate amount of sleep 2 | Moderate | |
Schedules and routines | - Consistent and relaxing bedtime routine | Strong |
- Daytime activities should not interfere with sleep | Moderate | |
Location | - Dark, cool, and quiet sleep location; limit distractions | Limited |
- Activities in bedroom restricted to quiet play and sleep | Limited | |
No Electronics in the bedroom or before bed | - No electronics in bedroom | Strong |
- Do not use electronics within a 1 h before bedtime | Limited | |
Exercise and diet | - Physical activity on a daily basis | Equivocal |
- Well-balanced and healthy diet | Limited | |
Positivity and relaxation | - Positive living atmosphere, free of conflict | Moderate |
- Child should feel relaxed and calm before bed | Limited | |
Independence falling asleep | - Encourage falling asleep and staying asleep without parent help | Strong |
Needs met during the day… equals Great sleep | - Satisfy emotional and physiological needs during daytime | Moderate |
Consider melatonin in children with | Sleep-onset insomnia and/or difficulty awakening up in the morning. |
Measure… | DLMO when possible before starting the treatment. |
Minimum age for administration | Administration after 6 months of age is generally considered safe. |
Time of administration in children | - If used as sleep inductor: 30 min before bedtime. |
- If used as chronobiotic: 2–3 h before DLMO or 3–4 h before actual sleep-onset time. | |
Dosage | If used as a sleep inductor: |
- start with 1–3 mg (up to 5 mg in adolescents); | |
- if needed, increase by 1–3 mg every 1–2 week until effect (maximum 3 mg if < 40 kg; up to 5–6 mg if > 40 kg (see text)). | |
If used as chronobiotic: | |
- start with a low dose of 0.2–0.5 mg; | |
- if needed, increase by 0.2–0.5 mg every week until effect; | |
- if no response after 1 week: increase dose by 1 mg every week until effect; | |
- when 1 mg is effective: try lower dose. | |
Treatment duration | - Treatment duration should be tailored to the specific patient but in general should not be less than 1 month; |
Stopping successful treatment too early may result in relapse of insomnia. | |
- Treatment can be withdrawn just before puberty (around 12 years of age) or shortly thereafter. | |
- Stop melatonin treatment once a year for one week (preferably in summer) after a normal sleep cycle is established. | |
When melatonin treatment is not effective/loses effectiveness over time | - Check timing of administration. |
- Be aware that loss of efficacy of melatonin treatment is most likely caused by slow melatonin metabolism: in some cases, dose reduction is warranted instead of dose escalation. | |
- Reconsider diagnosis: look for neuropsychiatric and medical comorbidities and treat them. | |
- Concomitant medications can influence melatonin metabolism: | |
e.g., ciprofloxacin, cimetidine, fluvoxamine (inhibitors) or carbamazepine, insulin, omeprazole (inducers). | |
If sleep maintenance problems after start of melatonin treatment | Melatonin dose is probably too high. |
Antihistamine | Dosage | Effects on Sleep | Refs |
---|---|---|---|
Diphenhydramine | 0.5 mg/kg up to 25 mg/day | ↓ SOL; ↓ arousal threshold | [111,112] |
Hydroxyzine | 0.5–1 mg/kg/day | ↓ SOL; ↓ arousal threshold | [113] |
Niaprazine | 1 mg/kg/day | ↓ SOL; ↓ arousal threshold; effect on sleep maintenance (e.g., ↑ TST) | [114,115] |
Most common side effects: daytime drowsiness, gastrointestinal disturbances (vomiting, constipation), paradoxical excitation, anti-cholinergic effects [25]. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Esposito, D.; Belli, A.; Ferri, R.; Bruni, O. Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments. Brain Sci. 2020, 10, 441. https://doi.org/10.3390/brainsci10070441
Esposito D, Belli A, Ferri R, Bruni O. Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments. Brain Sciences. 2020; 10(7):441. https://doi.org/10.3390/brainsci10070441
Chicago/Turabian StyleEsposito, Dario, Arianna Belli, Raffaele Ferri, and Oliviero Bruni. 2020. "Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments" Brain Sciences 10, no. 7: 441. https://doi.org/10.3390/brainsci10070441
APA StyleEsposito, D., Belli, A., Ferri, R., & Bruni, O. (2020). Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments. Brain Sciences, 10(7), 441. https://doi.org/10.3390/brainsci10070441