TABLE 1.
Circadian dysfunctions in ASD.
| ASD patients and control | Circadian biomarkers | Findings | References |
| Age: Mean = 9 years Number(sex): 19 (M), 3 (F) Control: Six adults (mean age = 30 years), 5 (M) and 1 (F); 27 children (mean age = 9 years), 15 (M) and 12 (F) Other factors: 15 highly developed and 7 poorly developed ASD cases based on IQ 60 | Cortisol in saliva and blood | Abnormal diurnal rhythm of salivary cortisol (higher peak in the morning) and lower response in dexamethasone suppression test in ASD vs. control, especially in poorly developed cases | Hoshino et al., 1987 |
| Age: 4–19 years, mean = 10.2 years Number(sex): 30 in total, no sex data Control: 106 children, aged 1–19 years, mean = 9.7 years; 17 adults, aged 20–55 years, mean = 35.5 years | Serotonin in blood | (1) Summer serotonin levels in ASD significantly are lower compared to other seasons. (2) Average serotonin level in ASD is significantly higher than controls. |
Badcock et al., 1987 |
| Age: 4–14 years, mean = 8.3 years, Number(sex): 14 (M), 4 (F) Control: 16 (M), 3 (F) | Cortisol in urine | Increased cortisol levels at all times of day, particularly morning to mid-afternoon | Richdale and Prior, 1992 |
| Age: Mean = 18 years Number(sex): 10 in total, no sex data Control: 15 parents, 1 grandparent, 9 siblings, and 10 unrelated healthy individuals Other factors: Control were significantly older than autism group | Melatonin in urine | Increased daytime melatonin level and ratio of daytime/nighttime melatonin levels compared to controls | Ritvo et al., 1993 |
| Age: 16–30 years Number(sex): 10 (M) Control: 5 matched in age and weight | Melatonin in blood | (1) Melatonin levels in ASD higher during the day and lower at night vs. controls (2) No differences in cortisol levels |
Nir et al., 1995 |
| Age: 3–23 years, mean = 9.2 years Number(sex): 42 (M), 20 (F) Control: 91 in total, aged 2–16 years, age and sex matched Other factors: Relatives of autism patients were also examined for serotonin levels | Serotonin in blood | (1) Higher serotonin levels in ASD vs. control above age 16 (2) No difference in serotonin levels between ASD and control below age 16 (3) Distribution of serotonin levels significantly more variable in ASD than control (4) Serotonin levels in control decrease with age, while serotonin levels in ASD is independent of age |
Leboyer et al., 1999 |
| Age: Mean = 8.5 years Number(sex): 12(M) Control: 10 (M), mean age = 9.2 years Other factors: Groups were matched on age and gender but not on IQ. Mean IQ of autism group = 77, and mean IQ of normal group = 114 | Cortisol in saliva | (1) No significant difference in mean cortisol daily variation between children with autism and typically developing children (2) Children with autism showed significantly increased response to a non-social stressor (mock MRI), while typically developing children showed no response in cortisol level |
Corbett et al., 2006 |
| Age: 14.8 ± 7 years Number(sex): 29 (M), 14 (F) Control: 45 (M), 30 (F), sex and age matched. Thirty four parents of ASD patients were also examined. | Asmt mutations, melatonin and serotonin in blood and platelets | (1) Non-conservative variations of Asmt (the gene encoding the last enzyme of melatonin synthesis) identified in ASD families but not in controls. Two polymorphisms located in the promoter were more frequent in ASD compared to controls associated with a decrease in ASMT transcripts in blood cell lines (2) Decreased in ASMT activity and melatonin levels in individuals with ASD and damped melatonin daily rhythms in ASD (3) Increased serotonin levels in ASD and their parents compared to controls (4) Poor sleep efficiency and higher arousal index but normal REM and slow wave sleep in patients with ASMT mutations |
Melke et al., 2008 |
| Age: Mean = 9.08 years, Range = 6.5–12 years Number(sex): 21(M), 1(F) Control: 19(M), 3(F) Other factors: Cortisol levels were measured in anticipation and response to a stressful event (mock-MRI) | Cortisol in saliva | (1) Children with autism showed consistently higher cortisol levels in the evening (2) Diurnal variations of cortisol are more inconsistent in autism individuals |
Corbett et al., 2008 |
| Age: Mean = 9.1 years Number(sex): 13(M), 2(F) Control: 21(M), 4(F), aged 6–12 years | Cortisol in saliva | No significant difference in the cortisol awakening response between individuals with high functioning autism and controls | Zinke et al., 2010 |
| Age: 2–5 years, mean = 3.75 years Number(sex): 22(M), 4(F) Control: 23(M), 3(F), mean age = 3.3 years | Cortisol in saliva | (1) Moderately increased mean cortisol secretion levels in autism children upon waking compared to controls (not statistically significant p > 0.05) (2) Mildly increased mean cortisol in autism children during daytime and evening compared to controls (not statistically significant p > 0.05) |
Kidd et al., 2012 |
| Age: Mean = 10.3 years Number(sex): 47 in total, 35 autistic disorder, 10 Asperger syndrome, five pervasive development, no sex data included Control: 50 in total, mean = 9.9 years | Cortisol in saliva | No differences in cortisol levels at any given time point for ASD children when compared with controls | Corbett and Schupp, 2014 |
| Age: Mean = 10.2 years Number(sex): 30(M), 6(F) Control: 23(M), 4(F), mean = 9.71 years | Cortisol in saliva | (1) Higher overall cortisol levels in ASD than control (2) Higher cortisol levels in ASD in the evening compared to controls (3) Flatter diurnal cortisol rhythm in some ASD children |
Tomarken et al., 2015 |
| Age: LFASD mean = 9.23 years, HFASD mean = 9.38 years Number(sex): LFASD 13(M), HFASD 16(M) Control: 14(M), mean age = 9.36 years | Cortisol in saliva | (1) Children with low functioning ASD (LFASD) demonstrated higher cortisol levels at morning, afternoon, and evening compared with children with high functioning ASD (HFASD) and normal children (2) Lower cortisol levels in HFASD individuals in the morning than typically developing individuals |
Putnam et al., 2015 |
| Age: Mean = 7.51 years Number(sex): 35(M), 8(F) Control: 30(M), 10(F), mean = 7.83 years | Cortisol in saliva and serotonin in blood | (1) Elevated cortisol levels in ASD compared with control (2) Elevated serotonin levels in ASD compared with control (3) Flattened cortisol diurnal rhythms in ASD compared with control |
Yang et al., 2015 |