Hollander 2010.

Study characteristics
Methods	Parallel trial of divalproex sodium versus placebo
Participants	Inclusion criteria: aged 5‐17 years outpatients met the DSM‐4 criteria for ASD CGI‐S score of at least 4 ABC‐I score of at least 18 Overt Aggression Scale‐Modified (OAS‐M) score of at least 13 seizure‐free for at least 6 months and on a stable dose of anticonvulsants other than divalproex sodium or related formulations non‐medicated children with a history of seizures and 6‐month seizure‐free, or with an abnormal EEG but no clinical seizures Exclusion criteria: pregnant or nursing mothers sexually active women of childbearing potential who are not using adequate birth control measures overall adaptive behavior scores < 2 years on the Vineland Adaptive Behavior Rating Scale active or unstable epilepsy any of the following past or present mental disorders: schizophrenia, schizoaffective disorder or organic mental disorders serious suicidal risk clinically significant or unstable medical illness that would contraindicate participation in the study, including hematopoietic or cardiovascular disease, pancreatitis, liver toxicity, and polycystic ovary syndrome history of encephalitis, phenylketonuria, tuberous sclerosis, fragile X syndrome, anoxia during birth, pica, neurofibromatosis, hypomelanosis of Ito, hypothyroidism, Duchenne muscular dystrophy, and maternal rubella history of the following: gastrointestinal, liver, or kidney, or other known conditions which will presently interfere presently with the absorption, distribution, metabolism, or excretion of drugs cerebrovascular disease or brain trauma clinically significant unstable endocrine disorder, such as hypo‐ or hyperthyroidism recent history or presence of any form of malignancy treatment within the previous 30 days with any drug known to a well‐defined potential for toxicity to a major organ clinically significant abnormalities in laboratory tests or physical exam likely to require electroconvulsive therapy or any other psychotropic medication during the study, unless otherwise permitted unable to tolerate taper from psychoactive medication if necessary history of hypersensitivity or severe side effects associated with the use of divalproex sodium, or an ineffective prior therapeutic trial of divalproex sodium (serum levels within range of 50‐100 ug/mL for 6 weeks) received any of the following interventions within the prescribed period before starting treatment: investigational drugs within the previous 30 days depot neuroleptic medication psychotropic drugs not permitted for concurrent use in the study within the previous 7 days fluoxetine within the previous 5 weeks any new alternative non‐medication treatments, such as diet, vitamins, and psychosocial therapy, begun within the previous 3 months any organic or systemic disease or patients who require a therapeutic intervention, not otherwise specified, which would confound the evaluation of the safety of the study medication currently reside in a remote geographical area who do not have regular access to transportation to the clinical facility Location/setting: not mentioned Sample size: 16 (intervention group), 11 (placebo group) Number of withdrawals/dropouts: placebo group 1 withdrawal; intervention group 1 withdrawal for lack of efficacy. Gender: 23 male, 4 female Mean age: 9.46 years IQ: placebo 76.1, intervention 52.92. Overall mean IQ 63.3 Baseline ABC‐I or other BoC: ABC‐I intervention group 20.3, placebo 22 Concomitant medications: 0% History of previous medications: details not provided
Interventions	Intervention (divalproex sodium) for 12 weeks: started at 125 mg/day for children weighing up to 40 kg and titrated to a maximum of 250 mg twice/day over 1 week. For children weighing ≥ 40 kg, the starting dose was 250 mg/day and titrated to a maximum of 500 mg twice/day over 1 week. Comparator (placebo) for 12 weeks: participants received a placebo comparative to the study drug divalproex sodium
Outcomes	Primary outcomes: irritability, measured using the ABC‐I subscale (Aman 1985) AEs Secondary outcomes: tolerability Timing of outcome assessments: AEs recorded at baseline then weekly for 4 weeks then biweekly for next 4 weeks
Notes	Study start date: not reported Study end date: not reported Source of funding: funded by NINDS R21 NS4 3979‐01, E Hollander, PI. Grant no. M01‐RR00071 from the National Centre for Research Resources (NCRR) Conflicts of interest: "Eric Hollander received consultation fees from Abbott, Neuropharm, Nastech, BMS, and Forest; received research grants from Abbott, and UBS Pharma; and has intellectual property related to oxytocin and memantine and ASD. Evdokia Anagnostou received a consultation fee by InteGragen. The rest of the authors have nothing to disclose". Trial registry: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The children were randomised in a 1:1 fashion
Allocation concealment (selection bias)	Unclear risk	Details not provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Details not provided except, quote: "all clinicians involved in efficacy or safety assessments were blinded to the randomisation condition", and "feedback on subjects randomised to placebo was based on a blocked schedule, so that all study clinicians remained blinded to the condition of randomisation."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Details not provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No direct mention of ITT methods to account for 3 participants who didn't complete intervention, however implied in the total number analysed
Selective reporting (reporting bias)	Low risk	Final ABC‐I scores were not provided however were on the clinicaltrials.gov website
Other bias	High risk	Quote: "adverse event monitoring took place every week for the first four weeks and every 2 weeks thereafter. Questions were focused on known side effects of divalproex sodium, followed by open‐ended questions."