|Reference||No. of Subjects||Patient Characteristics||Intervention||Comparison||Length of Follow-up||Outcome Measure(s)||Results||Funding Source||Comments|
|Trials of pyridoxine/magnesium|
|Findling et al. (1997)||12 patients enrolled, 10 completed the study (2 patients withdrew during two week lead-in period due to refusal to take study medicine).||Aged 3-17, met Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for autistic disorder, all living at home with a parent/guardian.|
Significant past or current medical or neurological disorder, use of a psychotropic agent within 3 months prior to start of study.
|Pyridoxine 30mg/kg/day (max. 1g) + Mg. oxide 10mg/kg/day (max. 350mg)|
Doses given twice daily at 8am and 12pm. All subject s received placebo for the first two weeks (baseline period), after which they were randomised and received either treatment or placebo for four weeks, and then the opposite for the next four weeks.
|Placebo (identical appearance, efforts made to match taste)|
At baseline, all subjects received placebo for 2 weeks in a single-blind fashion before randomisation.
|Subjects were evaluated every other week for a 10-week period.||Childhood Autism Rating Scale (CARS),|
Clinical Global Impression scale (CGI scale),
Children’s Psychiatric Rating Scale(CPRS),
Obsessive Compulsive Scale (OCS).
|ANOVA revealed no statistically significant effects of vit.B6 + Mg. on any of the outcome measures.|
50% of patients had a 30% reduction in CPRS score during the placebo lead-in phase of the study.
|Not specified||Jadad score = 4|
|Kuriyama et al. (2002)||15 patients were recruited, but four met the exclusion criteria. 11 completed the baseline study, 3 were then excluded based on immeasurable IQs.|
Therefore 8 patients were randomised (4 in treatment group, 4 in placebo).
|Met DSM-IV criteria for PDDs, had expressive verbal disorders, developmental motor coordination disorders and hypersensitivity to sound, aged 6-17.|
Exclusion criteria: History of epilepsy or an epileptiform EEG, use of a psychotropic agent within 3 mths of starting the study, inability to measure IQ, brain image abnormalities on MRI, history of homocystinuria or fragile-x syndrome. In both groups, one child had AS and three PDD-NOS.
|Pyridoxine 100mg in powder form once daily for the first 2 weeks, 100mg twice daily for the second 2 weeks (after breakfast and after dinner).||Placebo (powder form, identical in appearance and taste).||Subjects were evaluated at baseline and after 4 weeks of treatment.||Changes in IQ scores (both verbal IQ and performance IQ) using the Wechsler Intelligence Scale for Children-III (WISC-III), social quotient (SQ) scores measured with the Social Maturity Scale (SM) test assessed by the subjects’ parents.||There was a statistically significant increase in verbal IQ in the vit.B6 group relative to the placebo group, although verbal IQ did increase in both groups (by 11.2 in the treatment group and by 6.0 in the placebo group). The difference was still significant after controlling for sex, age, body weight, interval between tests and baseline verbal IQ using ANOVA.|
No significant difference in performance IQ and SQ scores was found.
|Not specified||Jadad score = 5|
Limited by small sample size and short-term nature
Mg was not given
|Tolbert et al. (1993)||15 patients were randomised.|
A further 5 subjects not receiving any treatment served as controls.
|Ages 6-18, all diagnosed with autism according to the DSM-III-R criteria, all residential students and receiving a standardised diet.|
No subjects had lactose intolerance, no pyridoxine deficiencies were identified.
|Pyridoxine 200mg/70kg/day in 50mg tablets in divided doses.|
Magnesium 100mg/70kg/day in 27mg tablets in divided doses.
|Placebo (matching tablets) and control.|
Group 1: treatment for 20 weeks then placebo for 10 weeks
Group 2: treatment for 10 weeks, placebo for 10 weeks, treatment for 10 weeks.
(after 5-week baseline period)
|Subjects were evaluated after baseline and after each of three 10-week blocks (i.e. 30 weeks)||Ritvo-Freeman Real Life Rating Scale for Autism (R-F)|
- quantitates 47 specific behaviours grouped into 5 subscales: sensory-motor, social, affective, sensory responses language.
Raters observed subjects involved in classroom activities from a room equipped with one-way mirrors and sound amplification.
|No significant differences among the three groups at any of the time points.|
There was a statistically significant reduction in scores across the time period for each group, possible due to other non-pharmacological therapy that patients were receiving throughout the trial.
|Not specified||Jadad score = 3|
This study specifically used much lower doses of pyridoxine than previous studies in an attempt to reduce the risk of peripheral neuropathies.
|Trials of dimethylglycine (DMG)|
|Bolman and Richmond (1999)||10 were recruited, 8 completed full testing.||Ages 4-30, diagnosed according to DSM-III-R criteria, not taking other medication within one month prior to the study.||DMG tablets, doses varied with weight (from 125mg/day for under 70lbs to 375mg/day for over 120lbs)||Look-alike placebos|
2-week baseline period, 4 weeks of either DMG or placebo, 2-week washout period, 4 weeks of placebo or DMG, 2-week baseline period.
|14 weeks (3 ½ months)||Campbell-NIMH 14-point Autism Rating Scale (ARS)(patients were videotaped weekly following a semi-structured set of guidelines in a playroom)|
An experimental 10-item checklist developed by Rimland
Individualised scales developed with help of parents (3 scales)
|Videotaping (ARS): no significant changes in behaviour observed.|
Experimental checklist: no significant differences between any of the study periods
Individualised scales: From a group total of 55 scale items, 5 showed improvement with DMG vs. placebo, 14 worsened and 36 showed no difference.
|Not specified||Jadad score = 3|
Only 3 out of 8 parents could correctly guess during which period their child had taken DMG or placebo (less than chance).
|Kern et al. (2001)||39 began the study, 37 completed it||Ages 3-11, diagnosis of autism or pervasive developmental disorder (DSM-IV)|
7 children were on psychoactive medications (held constant throughout the study).
|Foil-wrapped 125mg DMG tablets (no. of tablets taken varied with weight, from 125mg/day for under 40lbs to 625mg/day for over 130lbs).||Identical placebo tablets (mannitol 125mg)||4 weeks||Behavioural Assessments (Vineland Maladaptive Behaviour Domain, Aberrant Behaviour Checklist)|
|Combined analysis of behavioural assessments revealed a significant improvement over the 4 weeks across all subjects (both placebo and treatment). There was no difference in improvement between the DMG group and the placebo group. No effect of DMG on any of the behavioural measures was observed.|
DMG treatment did not affect the neurological status.
|Not specified||Jadad score = 4|
Parents reported improvement in 58% of the DMG group and 53% of the placebo group.
Parents reported worsening in 16% of the DMG group and 32% of the placebo group
|Trials of ascorbic acid|
|Dolske et al. (1993)||18|
(13 male and 5 female).
|Inclusion: subjects diagnosed under the DMS-ІІІ-R criteria by two independent child psychiatrists, no lactose intolerance and plasma ascorbate levels "/>30µg/ml i.e. within normal range. Prior to the initiation of the study, subjects ascorbic acid supplementation ranged from 0-4g/70kg/day.|
Participants were aged between 6 and 19 years (mental age ranged from 2.0-6.7, IQs ranged from <20-65).
Subjects received a standardised diet throughout the duration of the study
Nine of the children were on neuroleptics concurrent with the study. Prior to the study, the neuroleptic doses had been stabilised and were maintained throughout the study.
|Ascorbic acid was administered at 8g/70kg/day in 500mg tablets, divided into two or three separate doses.|
Initially all subjects received ascorbic acid for a ten-week block.
After the first ten-week block, half the subjects were randomly assigned to continue to receive the ascorbic acid (Group 1) and the other half to receive a placebo (Group 2) for an additional ten weeks.
For the final ten weeks the treatments were reversed.
|Matching placebo tablet (film coated and identical in appearance).||Each treatment phase lasted 10 weeks and behaviours were rated weekly using the R-F scale.|
The weekly R-F scores (total and each subscale) in each 10-week block were averaged for each subject.
30-week trial overall.
|R-F was used as an instrument to determine drug treatment evaluation.|
Raters observed subjects participating in routine classroom activities from an observation room equipped with one-way mirrors and sound amplification.
|Comparison of total scores revealed a significant interaction when comparing Phase 2 and Phase 3 (p=0.02).|
Behaviour worsened in group 1 when going from ascorbate (Phase 2) to placebo (Phase 3), where as behaviour improved in group 2 when going from placebo (Phase 2) to ascorbate (Phase 3).
On the sensory motor scale (subscale 1), a significant interaction was found (group x phase 2 and 3) p=0.01. No other subscales revealed significant findings for main effects of group and phase interaction.
There were no significant differences (p"/>0.05) between R-F total scores and subscales of children receiving vs not receiving neuroleptic medication during the initial 10-week phase of the trial. Therefore this medication variable was not included in the subsequent analyses.
|Not stated||Jaded score= 2|
Article did not report any adverse effects.
Small sample size, hetero-geneous population, lack of ascorbate-free baseline, confound-ing neuroleptic variable, lack of different multiple dependent measures.
|Trials of vitamin B12|
|Bertoglio et al. 2010 ||30 cases||Children aged 3-8 diagnosed with autism with DSM-IV–TR and Autism Diagnostic Observation Schedule (ADOS) plus non-verbal IQ ≥49 measured by Wechsler Preschool and Primary Scale of Intelligence, Mullen Scales of Early learning or Wechsler Intelligence Scale for Children.||Methyl-cobalamin 64.5 μg/kg sc for 6 wks followed by cross-over for 6 wks (no washout period).||Placebo||12 week trial was followed by 6 month open label for 22 cases||Plasma GSH and GSH:GSSH linked to Global Clinical Impressions Score and other objective behavioural measures||Overall, no significant difference in GSH, GSH: GSSH or behavioural outcomes.|
No serious adverse events were reported, only hyperactivity and increased mouthing of objects.
|Institute of the Univer-sity of California, Davis Medical Centre||Jadad score = 4|
Increased GSH, & GSH:GSSH and improved behavioural outcomes in 9/30 children which were identified as a “responder group”.
|Trials of multivitamin supplements|
|Adams et al. (2004)||25 subjects were enrolled, 5 dropped out for varying reasons (20 completed - 9 in placebo group, 11 in supplement group)||Ages 3-8 yrs, diagnosis of ASD by a psychiatrist, no changes in any treatment therapies within 2 months prior to the start of the study, no prior use of a multivitamin/mineral supplement other than a standard children’s multivitamin/mineral.||Spectrum Support II -dosage was increased to maximum over 24 days and then held constant until day 34. Gradual transition during days 35-50 to Spectrum Support III which was continued until day 90.|
1ml/5lbs bodyweight three times daily with food.
|Placebo, matched to colour and consistency.||3 months||Global Impressions survey filled out by mothers||Mothers reported statistically significant improvements in sleep and GI symptoms in those children taking the supplement versus placebo.||Not specified||Jadad score = 4|
Spectrum support is a liquid multi-vitamin prepara-tion with a moderate level of vit.B6 and no copper
|Trials of probiotics|
|Parracho et al. (2010)||39 subjects, Group I (n=19), Group II (n=20) commenced the study. 17 participants withdrew before end of first arm, 8 from group I and 9 from group II. 3 subjects withdrew due to adverse effects, 1 with rash, 1 with diarrhoea and 1 with weight loss in feeding period. A further 2 subjects withdrew after first feeding arm and 3 after first washout. 17 subjects completed study (9 from group I and 8 from group II).||Children with ASD aged 4-16y ||Lactobacillus plantarum WCFS1|
(4.5x1010 colony-forming units per capsule). Probiotic feeding for 3 wks followed by cross-over for 3 wks (3 week washout period).
|Placebo||12 weeks||DBC administered immediately prior to commencing the feeding period i.e. baseline (B1), at the end of each feeding (F1 & F2) and washout period (W1 & W2).|
Two faecal samples were taken in the week prior to the study (commencing B1 & B2) and at F1, F2, W1 and W2 and bacterial populations examined.
Bowel function and GI symptoms were also determined.
|The overall indicator of behavioural/emotional disturbances i.e. Total Behaviour Problem Score (TBPS) was not significantly different between the two feeding periods.|
Probiotic feeding resulted in a higher percentage of ‘formed’ stool samples
(73.3 %) compared to the placebo feeding (64.8 %), whilst the percentage of ‘hard’ stool samples was lower during probiotic feeding.
No significant differences were observed between probiotic and placebo for GI symptoms (abdominal pain, intestinal bloating and flatulence)
|Not stated||Jadad score = 5|
Encapsulation of both placebo and probiotic, and blind coding of the capsules, was performed by Orafti (Belgium).
Adverse effects monitored for.
Lactobacillus plantarum WCFS1 and the placebo were supplied by Nizo Food Research, The Nether-lands.
High drop-out rate from study affected statistical power
|Trials of digestive enzymes|
|Munasinghet al. (2010)||43 subjects, 27 completed intervention. 3 were lost to follow up; 2 from Sequence 1 (S1) & 1 from Sequence (S2). 1 subject withdrew due to family issues (S1), 4 because of perceived behaviour deterioration (3 from S1 & 1 from S2), 5 due to difficulties with capsule administration (4 from S1 & 1 from S2) and 3 gave no reason (S2).||Children diagnosed with AD or PDD-NOS with the DSM-IV. Mean age was 69.4 months.||Digestive Enzyme|
S1 received Peptizyde TM for 3 months,
then crossed over and received placebo.
S2 received placebo for 3 months, then crossed over and received PeptizydeTM for 3 months. (1 week washout period between treatment sequences)
|Placebo||6 months and 1 week||Global Behaviour Rating Scale (GBRS), Additional Rating scale (ARS), Language Development Survey (LDS)||No significant difference on the GBRS, ARS and LDS questionnaires. A small statistically significant improvement on enzyme therapy was seen for the food variety scores that was not deemed clinically significant.||Not stated||Jadad score = 5|
Enzyme and placebo provided by Houston Nutraceuticals
|Trials of polyunsaturated fatty acids (PUFAs)|
|13 subjects, PUFA (n =7) or placebo|
(n =6). One individual from the placebo group withdrew from the trial after 2 weeks because of GI complaints and lack of symptom improvement.
|Children with average age 10.4, (5-17y) diagnosed with autism with DSM-IV–TR and ADOS||7X 1g capsules of Menhaden fish oil containing 840 mg eicosa-pentaenoic acid (EPA), 700 mg docosa-hexaenoic acid (DHA) & 7 mg Vitamin E (i.e. 1.54g of PUFA/day) for 6 weeks||Placebo i.e. coconut oil with 1 mg fish oil and 1 mg vitamin E||6 weeks||Aberrant Behavior Checklist (ABC)||Non-significant trends towards improvement.|
Mild adverse events reported included fever in the experimental group and headache and insomnia in the placebo group.
|Not stated||Jadad score = 4|
Small sample size
Trends for improve-ment in hyper-activity, but not statisticallysignificant.
Omega Protein Co-operation, provided medication
|Bent et a. (2010)||25 subjects included in analysis, PUFA (n=13) or placebo (n=12). PUFA group, lost to follow-up (n=1, disliked taste), discontinued intervention (n=4, 2 disliked taste, 1 rash, 1 GI symptoms). Placebo group, lost to follow-up (n=1, blood draw anxiety), discontinued intervention (n=2, 1 disliked taste, 1 increased self-stimulatory behaviour)||Children ages 3-8 diagnosedwith ASD (with the ADOS, social communication questionnaire (SCQ) & DSM-IV-TR) and hyperactivity (with the ABC)||PUFAs were provided|
as orange-flavoured pudding packets (Coromega_, Vista,
CA) containing 650 mg of omega-3 fatty acids, including
350 mg of EPA and 230 mg of
DHA, given twice daily for a daily
dose of 1.3 g of PUFAs (and 1.1 g of
DHA/EPA) for 12 weeks.
|Placebo packets had the same orange-flavoured|
pudding with an identical appearance and taste, but
included safflower oil instead of the PUFAs.
|12 weeks||ABC (hyperactivity was primary outcome measure)|
Peabody Picture Vocabulary Test
Social Responsiveness Scale
Behavioral Assessment System for Children
Impression-Improvement (CGI-I) scale.
|Overall there were no statistically significant changes in any of the outcome measures.|
Hyperactivity as measured on the ABC improved 2.7 (+/-4.8) points in the PUFA group compared to 0.3 (+/-7.2) points in the placebo group (p = 0.40; effect size = 0.38) but was not statistically significant.
Speaks, the Higgins Family Found-ation, The Emch Found-ation, The
Taube Foundation,NIH/NCRR UCSF-CTSI Grant Number UL1
RR024131 (Dr. Bent) and the MIND Institute.
|Jadad score = 5|
Small sample size (pilot study)
Correl-ations were found between decreases in five fatty acid levels and decreases in hyperactivity.
Treatment was well tolerated.
|Trials of melatonin|
|Garstang & Wallis (2006)||7 children completed the study.|
11 children were initially enrolled (2 discontinued the study after the trial was suspended as placebo capsules were empty, 1 dropped out because of a house move and 1 dropped out because she was involved in a child protection enquiry.
|Children with a diagnosis of ASD (by a paediatrician or psychiatrist) aged 4-16, with significant difficulties sleeping at night||Melatonin 5mg, given at bedtime for 4 weeks||Placebo||No follow-up||Parents kept daily sleep logs from which the primary outcome measures were sleep latency, total hours of sleep, and number of night awakenings.||Mean and 95% confidence interval (CI) reported. There was a decrease in mean sleep latency, wakings per night and increased total sleep time with melatonin compared to baseline & placebo|
Sleep latency : Baseline 2.60 h [95% CI 2.28-2.93]; Placebo 1.91 h [1.78-2.03]; melatonin 1.06h [0.98-1.13]
Wakings per night: Baseline 0.35 [0.18-0.53]; Placebo 0.26 [0.20-0.34]; melatonin 0.08 [0.04-0.12]
Total sleep : Baseline 8.05 h [7.65 - 8.44]; Placebo 8.75 h [8.56-8.98]; melatonin 9.84 h [9.68-9.99]
|Coventry primary care trust|
The melatonin and placebo were supplied free of charge by Penn Pharmaceuticals Ltd.
|Jadad score = 4|
Possible unblinding due to problems with placebo capsules.
Statistical methods were not clearly described
Adverse effects not described
Small sample size
|Wright et al. (2011)||20 subjects were enrolled, 17 included in analysis.||Children diagnosed with ASD based on ICD-10 and confirmed by Autism Diagnostic Interview—Revised (ADI) or ADOS if necessary. Included 14 with autism, 4 atypical autism and 2 with AS. Children had all been referred for serious sleep problems. Children were aged 4-16 years and not taking psychotropic medication.||2 mg and titrated up to 10mg standard release melatonin, 1 hour prior to bedtime for 3 months||Placebo||Parents completed sleep diaries daily which were collected monthly for 9 months. Primary outcome measures were sleep latency, total sleep time, and number of wakenings|
Sleep Difficulties Questionnaire, Developmental Behaviour Checklist (DBC) and General Health Questionnaire collected at the start and end of each 3-month period of medication/
placebo and on completion. A Side Effects Questionnaire was completed at start, end and at end of each 3-month period of medication/
|Melatonin significantly improved sleep latency (by an average of 47 minutes, p=0.004) and total sleep (by an average of 52 minutes, p = 0.002) compared to placebo, but not number of night awakenings p = 0.209. There was a statistically significant difference in the total score of the DBC of 6.0 between melatonin and placebo (p=0.05). There was a significant difference in favour of melatonin for the dysomnias subscale of the Sleep Difficulties questionnaire p=0.041) but not other subscales.|
Adverse effect profile low and similar between arms.
|York Innov-ations Fund and the London law Trust||Jadad score = 5|
Placebo was manufactured to be identical in appearance and constitution as the active form.