Chez 2020.

Study characteristics
Methods	8‐week cross‐over trial of dextromethorphan + quinidine versus placebo
Participants	Inclusion criteria: 18–60 years of age diagnosis of ASD based on DSM‐4‐TR criteria, developmental history, and autism diagnostic observation scale (ADOS) or confirmed to have ASD during childhood through similar methods. demonstrated behavioural irritability or rapid mood changes that correlated with labile emotional state (frontal lobe type perseveration issues) have a collateral informant who attended visits and answered questionnaires pertaining to participants’ behaviour no medication changes for 30 days or new medications during the course of the study with the exception of medications for non‐related conditions Sexually active women of child‐bearing potential were required to be on reliable form of contraception Exclusion criteria: "participants who had uncontrolled epilepsy (as defined as having clinical convulsive episodes within the past 6 months) prior to the study or cardiovascular conditions including cardiac or structural malformation heart fail‐ure, prolonged QT interval (>450 for males and >470 for females), history of torsades de pointes, or AV [atrioventricular] blocks were excluded". "Other exclusion criteria included pregnancy, hepatitis, bone marrow depression, thrombocytopenia, lupus‐like syndrome, head injuries, brain tumors; genetic disorders other than known genetic variants of autism, frontal lobe brain structural abnormalities, known allergy to dextromethorphan or quinidine, concurrent or recent (within 30 days) use of MAOI antidepressants, lamotrigine, felbamate or other NMDA agonists or antagonists; and any clinically significant physical or neurological conditions that could compromise the study or be detrimental to the subject. Patients with ASD who also had Fragile X, Downs, or Rett Syndrome were excluded." Location/ setting: single‐centre study in the USA Sample size: 15 were randomised although 7 in each group received at least 1 dose of intervention or placebo. Reasons for dropouts: 2 participants withdrew after 17 weeks. Both had collateral informants who decided to withdraw from the study due to behavior deterioration. Mean IQ: details not provided Mean age: 21.92 (3.30) years Gender: 3/14 were female Baseline ABC‐I or other BoC scale: dextromethorphan + quinidine 17.42 (9.23); placebo 17.5 (11.74) Concomitant medications: participants were not allowed to use MAOI antidepressants, lamotrigine, felbamate or other NMDA agonists or antagonists. Previous medications: not reported
Interventions	Intervention: participants received 20 mg dextromethorphan/10 mg quinidine in tablet form (Nuedexta) once daily for 7 days and then every 12 h for the next 7 weeks. Comparator: equivalent placebo for 8 weeks
Outcomes	Primary outcomes: ABC‐Irritability (Aman 1985) Secondary outcomes: tolerability Timing of outcome assessments: phase 1: baseline and week 8 Phase 2: baseline (after 4 week washout) and week 8
Notes	Study start date ‐ details not provided Study end date ‐ details not provided Funding: "This study was supported by an investigator initiated research Grant from Avanir Corporation (Grant No. 947135‐1107629)" Conflicts of interest: "Dr. Michael Chez has been a speaker for pediatric epilepsy issues for Eisai, Lundbeck, UCB, and Sunnovion for the past 2 years. No other authors have any conflicts of interest".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not provided
Allocation concealment (selection bias)	Unclear risk	Details not provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The parents, neuropsychologists, clinical research coordinators (CRC), and investigators were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The parents, neuropsychologists, clinical research coordinators (CRC), and investigators were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low attrition and all participants accounted for
Selective reporting (reporting bias)	Unclear risk	Without a clinical trial record or protocol, it is difficult to know if all outcomes were reported.
Other bias	High risk	Pharma funded ‐ Avanir Corporation