Author Year Type and duration of study Sample size Type of intervention Comparators Dose Outcome measure Findings Comments Omega 3 Amminger et al. [22 ] 2007 Randomized, double blind, placebo controlled, parallel group Duration: 6 weeks (M 13) Age: 5–17 yearsOmega 3 Placebo One drop-out from this group 0.84 g/day EPA and 0.7 g/day DHA ABC No significant difference between the two groups No details about blinding Small sample size Power analysis not reported Bent et al. [23 ] 2011 Randomized, double blind, placebo controlled, parallel group Duration: 12 weeks (M 24; F 3) Age: 3–8 yearsOmega 3 Drop-out Placebo Drop-out 0.7 g/day EPA and 0.46 g/day DHA ABC, PPVT-III, EVT, SRS, BASC, CGI-Improvement No statistically significant difference Only per-protocol analysis Small sample size Short study duration Bent et al. [24 ] 2014 Randomized, double blind, placebo controlled, parallel group Duration: 6 weeks (M 50; F 7) Age: 5–8 yearsOmega 3 Placebo 1.3 g/daily of omega 3 (1.1 g/day of EPA plus DHA) ABC, CGI, SRS No statistically significant difference Small sample size Short study duration Meguid et al. [25 ] 2008 Open label Duration: 3 months (M 18; F 12) Age: 3–11 yearsOmega 3 None 240 mg/day DHA; 52 mg/day EPA; 68 mg/day Omega-6 fatty acids CARS Improvement in 20 children Statistical analysis incorrect (conducted only on children which showed a reduction in symptoms) Open label design Small sample size Multicomponent intervention (also omega 6) Politi et al. [26 ] 2008 Open label Duration: 6 weeks (M 50; F 7) Age: 18–40 yearsOmega 3 None 0.93 g/day EPA plus DHA, 5 mg/day vitamin E Rossago behavioral checklist No significant change from baseline Small sample size Short study duration Open label design No standardized outcome measure Voigt et al. [27 ] 2014 Randomized, double blind, placebo controlled, parallel group Duration: 6 months (M 40; F 8) Age: 3–10 yearsOmega 3 Placebo 200 mg/day DHA CGI-Improvement scale, CDI, ABC, BASC No significant difference between active group and placebo Small sample size Low dosage Vitamins Findling et al. [28 ] 1997 Randomized, double blind placebo controlled, crossover Duration: 8 weeks (M 11; F 1) Drop-out Age: 3–12.9 yearsVitamin B6-magnesium Placebo B6: 30 mg/kg/day (max = 1 g/day); Mg: 10 mg/kg/day (max = 350 mg/day) CARS, CGI, CPRS, OCS No difference between the two groups Small sample size Short study duration Multicomponent intervention Per protocol analysis Kuriyama et al. [29 ] 2002 Randomized double blinded placebo controlled parallel group Duration: 4 weeks Entered the study only (M 4; F 4) Drop-out Age: 3–12.9 yearsVitamin B6 Placebo B6: 200 mg/day IQ (WISC-III) and SQ (SM) No difference between active group and placebo Small sample size High attrition rate Unclear characterization of patients “children with PDDs who exhibit clinical features similar to those of pyridoxine dependent epilepsy but do not have a history of seizures” Clinical characterization unclear (only PDD) Tolbert et al. [30 ] 1993 Randomized double blind placebo controlled, asymmetric crossover with 10 week treatment blocks (B6/Mg 20 w-placebo 10 w; or B6/Mg 10 w-placebo 10 w-B6/Mg 10 w) Duration: 30 weeks (M 10; F 5) Age: 6–18 yearsVitamin B6-magnesium Placebo B6: 200 mg/70 kg; Mg: 100 mg/70 kg RLRS No difference No information on placebo Presence of a control group, but not randomized Small sample size Low dosage of B6/Mg Asymmetric study design Bertoglio et al. [31 ]
2010 Randomized, double blind, placebo controlled, crossover Duration: 12 weeks (M 28; F 2) Age: 3–8 yearsMethyl B12 Placebo 64.5 mcg/kg every three days CGI-I, PIA-CV, CARS, PPVT-III, ABC, CBC, Stanford Binet Fifth Edition Routing Subsets, MCDI No significant difference between active treatment and placebo Small sample size Short study duration Improvement only in post hoc analysis Frye et al. [32 ] 2013 Open label trial Duration: 3 months (gender not explicitly reported) Drop-out Age: 4–6 yearsMethyl B12 vitamin plus folinic acid None 75 g/Kg methylcobalamin every three Folinic acid (400 g) twice daily Vineland Improvement in all Vineland subscales Only patients with abnormal redox metabolism were included High attrition rate Statistical analysis only performed on completers Small sample size Dolske et al. [33 ] 1993 Randomized double blinded placebo controlled, crossover with asymmetric design with 10 w block (randomly assigned to vitC-vitC-placebo or vitC-placebo-vitC) Duration: 30 weeks Age: 3–8 yearsVitamin C Placebo 8 g/70 kg/day RLRS Significant improvement in vitC treated Small sample size Short study duration Adams et al. [34 ] 2011 Randomized double blinded placebo controlled trial Duration: 3 months (M 125; F 16) Age: 5–16 yearsMultivitaminic supplement Drop-out Placebo Drop-out Each supplement was titrated to be over the recommended daily allowance but under the tolerable upper limit PDD-BI, ATEC, SAS, parent-rated behaviors Improvement of parent-rated irritability in the active group No power calculation High attrition rate Only per-protocol analysis Danfors et al. [35 ] 2005 Randomized, double blind, placebo controlled, crossover Duration: 6 months (M 12) Age: 4–7 yearsTetrahydrobiopterin (BH4) Placebo 3 mg/kg/day CARS (baseline, 3 and 6 month) Small changes in CARS total score Small sample size Only post-hoc analysis reveals significant changes in CARS subdomain Frye et al. [36 ] 2013 Open label Duration: 16 weeks (M 9; F 1) Age: 2–6 years Children must have low cerebrospinal fluid level of BH4Tetrahydrobiopterin (BH4) Drop-out None 20 mg/kg/day PLS, SRS, CARS, ASQ, Vineland Significant improvement in PLS, CARS, ASQ, and Vineland Open label Small sample size High attrition rate (20%) High tetrahydrobiopterin dose (usually 1–6 mg/kg/day) Klaiman et al. [37 ] 2013 Randomized, double blind, placebo controlled, parallel group Duration: 16 weeks Age: 3–7 yearsTetrahydrobiopterin (BH4) Placebo 20 mg/kg/day CGI, PLS, ABC, SRS, Vineland No significant difference between the two groups Improvement only in post hoc analysis on secondary measures High tetrahydrobiopterin dose (usually 1–6 mg/kg/day) L-carnosine Chez et al. [38 ] 2002 Randomized double blinded placebo controlled Duration: 8 weeks (M 21; F 10) Age: 3–12 yearsL-Carnosine Placebo 800 mg/day CARS, GARS, CGI Expressive and Receptive One-Word Picture Vocabulary tests, Significant improvement in the active group in GARS and in the Receptive One-Word Picture Vocabulary test Small sample size No power calculation Half of the subjects were on stable dosage of valproic acid Flavonoids
Taliou et al. [39 ] 2013 Open label Duration: 26 weeks (M 42; F 8) Drop-out Age: 4–10 yearsFlavonoid 1 capsule/10 Kg/day None Luteolin (100 mg/capsule), quercetin (70 mg/capsule), and the rutin (30 mg/capsule) Vineland, ABC, ATEC, CGI-improvement Improvement in Vineland and ABC scores Open label design Small sample size High attrition rate Probiotics
Kałuzna- Czaplińska and Błaszczyk [40 ] 2012 Open label Duration: 2 months (M 20; F 2) Age: 4–10 yearsProbiotic 1 capsule twice daily None Lactobacillus acidophilus (strain Rosell-11, containing 5 × 109 CFU/g)Observer rated autism core symptoms Improvement Open label design All children have gastrointestinal problems Other CAM treatments were used concomitantly Small sample size No standardized outcome measure Enzyme supplementation Munasinghe et al. [41 ] 2010 Randomized double blinded placebo controlled crossover Duration: 6 months (M 36; F 7) Drop-out Age: 3–8 yearsDigestive enzyme supplement Placebo Peptizyde (Peptidase, Protease 4.5 and Papain) two capsules with each meal GBRS, ARS of gastrointestinal symptoms, and the Rescorla LDS No difference High drop-out rate Not clear if intention-to-treat or per-protocol analysis Not all outcome measures were standardized Herbal remedies Hasanzadeh et al. [42 ] 2012 Randomized double blinded placebo controlled parallel group Duration: 10 weeks (M 39; F 8) Age: 4–12 years All children were on risperidone 2-3 mg/day according to weightGinkgo biloba (M 19; F 4) Placebo (M 20; F 4) 80 mg/day if weight <30 kg; otherwise 120 mg/day ABC No difference Small sample size Short study duration Only one outcome measure Miyaoka et al. [43 ] 2012 Open label Duration: 12 weeks (M 22; F 18) Age: 8–40 yearsYokusan None 5.0–7.5 g/day CGI-Severity, ABC Improvement in CGI and the irritability subscale of ABC Open label design Small sample size Chan et al. [44 ] 2014 Open label Duration: 6 months (M 26; F 4) Age: 7–17 yearsBornel and Borax nasal drops None 10 mL/day BRIEF, Tower of California, CCTT, CPRS, event-related EEG assessment Improvement Not placebo controlled Open label design Small sample size Statistical analysis not optimal