Table 2.
Therapeutics for sleep disturbances in ASD.
| Ligand | Primary Target (s) | Type | Action | Participants | Effect on Sleep | Reference |
|---|---|---|---|---|---|---|
| Melatonin Agonists | ||||||
| Melatonin | MT1 receptor MT2 receptor |
Agonist | Full Agonist | n = 107; 2–18 year olds with ASD | Improved sleep in 60% of participants | Andersen et al. (2008) |
| n = 146; 3–15 year olds with NDD, including ASD | Improved total sleep time, reduced sleep latency | Gringras et al. (2012) | ||||
| n = 24; 3–10 year olds with ASD, AS, PDD, PDD-NOS | Reduced sleep latency | Malow et al. (2012) | ||||
| n = 22; 3–16 year olds with ASD | Reduced sleep latency, improved sleep duration; no reduction in night awakenings | Wright et al. (2011) | ||||
| n = 12; 2–15 year olds with ASD, FXS, ASD + FXS, FX premutation | Reduced sleep latency, improved sleep duration, no difference in night awakenings, earlier bedtimes | Wirojanan et al. (2009) | ||||
| n = 11*; 4–16 year olds with ASD | Reduced sleep latency, improved total sleep time; reduced number of night awakenings. *Discontinued at 7 participants when discovered placebo capsules were empty |
Garstang and Wallis, 2006 | ||||
| n = 9; 2–11 year olds with ASD | Reduced sleep latency, improved total sleep duration | Gupta and Hutchins (2005) | ||||
| n = 9; 4–17 year olds with RS | Reduced sleep latency, improved total sleep time, sleep efficiency | McArthur and Budden (1998) | ||||
| n = 6; 19–52 year olds with ASD | Reduced sleep latency, night awakenings; increased total sleep time | Galli-Carminati et al. (2009) | ||||
| n = 2; 7, 13 year old with RS | Reduced sleep latency, improved sleep maintenance | Miyamoto et al. (1999) | ||||
| n = 1; a 17 year old with AS | Improved sleep maintenance; minimized night awakenings | Horrigan and Barnhill (1997) | ||||
| n = 1; a 10 year old with RS | Reduced sleep latency; reduced night awakenings | Yamashita et al. (1999) | ||||
| n = 1; a 14 year old with ASD | Improved sleep duration, daily sleep-wake rhythm | Hayashi (2000) | ||||
| n = 1, a 12 year old with AS | Reduced sleep latency; reduced night terrors, night awakenings | Bottanelli et al. (2004) | ||||
| Melatonin-CR | MT1 receptor MT2 receptor |
Agonist | Full Agonist | n = 160, 4–10 year olds with ASD | Reduced sleep latency, improved total sleep time; reduced night awakenings | Cortesi et al. (2012) |
| n = 50, 2–18 year olds with NDD including ASD (cross-over trial) | Improved total sleep duration, reduced sleep latency | Wasdell et al. (2008) | ||||
| n = 47, 2–18 year olds with NDD including ASD (open-label phase) | Improved sleep efficiency, longer sleep episodes | Wasdell et al. (2008) | ||||
| n = 25; 2–9 year olds with ASD | Improved sleep onset, sleep duration, night-time awakenings, parasomnias and daytime sleepiness | Giannotti et al. (2006) | ||||
| Melatonin-PedPRM | MT1 receptor MT2 receptor |
Agonist | Full Agonist | n = 125, 2–17 year olds with ASD (96.8%) or SMS (3.2%) | Improved total sleep time, reduced sleep latency; reduced sleep disturbances | Gringras et al. (2017) |
| n = 125, 2–17 year olds with ASD (96.8%) or SMS (3.2%) | Improved sleep duration, reduced sleep latency | Schroder et al. (2019) | ||||
| n = 95, 2–17 year olds with ASD, neurogenic disorders | Improved total sleep time, reduced sleep latency, improved sleep quality; reduced night awakenings | Maras et al. (2018) | ||||
| n = 80, 2–17 year olds with ASD (96%) or SMS (4%) | Improved sleep disturbances, quality of sleep, caregiver satisfaction with children sleep patterns | Malow et al. (2021) | ||||
| Ramelteon | MT1 receptor MT2 receptor |
Agonist | Full Agonist | n = 3; 9–12 year olds with ASD | Improved latency to persistent sleep, total sleep time | Kawabe et al. (2014) |
| n = 2; 7, 18 year olds with ASD | Reduced sleep latency, improved sleep maintenance; reduced night awakenings | Stigler et al. (2006) | ||||
| α-Agonists | ||||||
| Clonidine | α2A-adrenoreceptor α2B-adrenoreceptor |
Agonist | Partial agonist | n = 19; 4–16 year olds with ASD, PDD, AS | Reduced sleep latency; reduced night awakenings | Ming et al. (2008) |
| n = 6; 6–14 year olds with ASD, PDD | Reduced sleep latency; Increased total sleep duration; reduced night awakenings | Ingrassia and Turk (2005) | ||||
| Guanfacine | α2A-adrenoreceptor α2B-adrenoreceptor α2C-adrenoreceptor |
Agonist Agonist Agonist |
Partial agonist Full Agonist Partial agonist |
n = 80; 3–18 years old with ASD, AS, PDD-NOS | Improved insomnia in 24% of patients | Posey et al. (2004) |
| Guanfacine-ER | α2A-adrenoreceptor α2B-adrenoreceptor α2C-adrenoreceptor |
Agonist Agonist Agonist |
Partial agonist Full Agonist Partial agonist |
n = 62; 5–14 year olds with ASD | No effect | Politte et al. (2018) |
| n = 1; 10 year old with ASD | Reduced sleep latency, improved sleep maintenance | Propper (2018) | ||||
| Antihistamines | ||||||
| Niaprazine | H1 receptor 5-HT2 receptor α1-adrenoreceptor |
Antagonist | – | n = 25; 2–20 year olds with ASD | Improved sleep disorders in 52% of patients | Rossi et al. (1999) |
| Antidepressants | ||||||
| Mirtazapine | α2C-adrenoreceptor α2A-adrenoreceptor α2B-adrenoreceptor 5-HT2C receptor 5-HT2A receptor |
Antagonist | – | n = 26; 3–23 year olds with ASD, AS, RS, PDD | Improved sleep quality | Posey et al. (2001) |
| n = 26; 5–17 year olds with ASD | No reduction in problematic sleep habits compared to placebo | McDougle et al. (2022) | ||||
| n = 1; 13 year old with ASD | Improved sleep | Nguyen and Murphy (2001) | ||||
| n = 1; 13 year old with ASD | Reduced sleep latency | Coskun and Mukaddes (2008) | ||||
| n = 1; 11 year old with ASD | Reduced sleep problems (combined with Aripiprazole) | Akbas and Akca (2018) | ||||
| n = 1; 15 year old with ASD | Improved sleep | Naguy et al. (2019) | ||||
| Trazodone | 5-HT2A receptor 5-HT2C receptor |
Antagonist | – | n = 1; 8 year old with ASD | Improved sleep | Rapin, 2001 |
| 1 year follow-up of Rapin (2001) | Continued to help with sleep | Parker and Hartman (2002) | ||||
| n = 1; 9 year old with AS | Reduced sleep latency | Bloomfield et al. (2015) | ||||
| Fluoxetine | SERT | Inhibitor | Inhibition | n = 1; 16 year old with ASD | Reduced insomnia | Cawkwell et al. (2016) |
| Fluvoxamine | SERT | Inhibitor | Inhibition | n = 1; 8 year old with AS | Reduced sleep disturbances | Furusho et al. (2001) |
| Paroxetine | SERT | Inhibitor | Inhibition | n = 1; 7 year old with ASD/PDD | Improved sleep | Posey et al. (1999) |
| Amitriptyline | H1 receptor M4 receptor M2 receptor M3 receptor M5 receptor SERT NET |
Antagonist Inhibitor |
– Inhibition |
n = 1; 6 year old with ASD | Improved sleep | Pollard and Prendergast (2004) |
| Antipsychotics | ||||||
| Risperidone | 5-HT2A receptor D2 receptor 5-HT1D receptor 5-HT1B receptor |
Antagonist | Inverse agonist – – – |
n = 56; 5–17 year olds with ASD | Improved sleep quality | Kent et al. (2013) |
| n = 23; 3–13 year olds with ASD, PDD-NOS, late-onset ASD | Improved sleep quality and/or duration | Capone et al. (2008) | ||||
| n = 11; 6–34 year olds with ASD | Reduced sleep latency, improved staying asleep | Horrigan and Barnhill (1997) | ||||
| n = 11; 7–17 year olds with ASD, PDD-NOS | Reduced sleep disturbances | Zuddas et al., 2000 | ||||
| n = 6; 3–13 year olds with ASD | Reduced sleep disturbances | Vercellino et al. (2001) | ||||
| n = 1; 16 year old with ASD | Upon withdrawal of risperidone, sleep worsened | Feroz-Nainar et al. (2006) | ||||
| n = 1; 10 year old with ASD | Improved sleeping throughout the night | Ivanov et al. (2006) | ||||
| n = 1; 3 year old with PDD | Improved sleep; reduced night awakenings | Doan (1998) | ||||
| n = 1; 5 year old with ASD | Improved sleep | Demb (1996) | ||||
| Aripiprazole | D2 receptor | Agonist | Partial Agonist | n = 32; 5–19 year olds with ASD | Improved sleep in 4/9 with sleep disorders | Valicenti-McDermott and Demb (2006) |
| n = 5; 5–18 year olds with PDD | Improved sleep | Stigler et al. (2004) | ||||
| n = 1; 11 year old with ASD | Reduced sleep problems (combined with Mirtazapine) | Akbas and Akca (2018) | ||||
| Quetiapine | D2 receptor 5-HT2A receptor |
Antagonist | – | n = 11; 13–17 year olds with ASD | Improved sleep disturbances, sleep quality | Golubchik et al. (2011) |
| n = 1; 16 year old with PDD-NOS | Improved sleep during manic state | Vijapura et al. (2014) | ||||
| n = 1; 17 year old with ASD | Improved sleep | Tufan and Kutlu (2009) | ||||
| Ziprasidone | 5-HT2A receptor D2 receptor 5-HT2C receptor |
Antagonist | – – Inverse agonist |
n = 1; 7 year old with ASD | Improved sleep pattern | Goforth and Rao, 2003 |
| Olanzapine | 5-HT2A receptor D2 receptor 5-HT2C receptor |
Antagonist | – – Inverse agonist |
n = 1; 6 year old with ASD | Improved sleep | Hergüner (2010) |
AS: Asperger's Syndrome; PDD: Pervasive Developmental Disorders; PDD-NOS: PDD-Not Otherwise Specified; FXS: Fragile-X Syndrome; RS: Rett-Syndrome; NDD: Neurodevelopmental Disorders; CR: Controlled-Release; PedPRM: Pediatric Prolonged Release Melatonin; SMS: Smith-Magenis Syndrome; ER: Extended Release; M# receptor: Acetylcholine receptor; D# receptor: Dopamine receptor.