Kowatch 2015.

Methods	Randomised double‐blind trial
Participants	Number of total participants/type of patients: 46 participants were randomised. Outpatient study Inclusion criteria: Sex: male and female Age: children (3 ‐ 7 years) Diagnosis: bipolar I diagnosis according to the DSM IV‐TR criteria, manic or mixed episode (with or without psychotic features) with a score ≥ 20 on the YMRS at the time of randomisation Exclusion criteria: Clinically significant or unstable hepatic, renal, gastroenterological, respiratory, cardiovascular, endocrine, immunological, haematological, or other systemic medical conditions; neurological disorders including epilepsy, stroke, or severe head trauma; clinically significant laboratory abnormalities on complete blood count (CBC) with differential, electrolytes, blood urea nitrogen (BUN), creatinine, hepatic transaminases, urinalysis, thyroid indices (T3, total T4, tree T4, thyroid‐stimulating hormone (TSH)) and electrocardiogram (ECG); mania caused by a general medical condition or substance‐induced mania; mental retardation (intelligence quotient (IQ) < 70); evidence of foetal alcohol syndrome or an alcohol‐related neurodevelopmental disorder; or schizophrenia or other psychotic disorders (including schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder caused by a general medical condition, substance induced psychotic disorder, psychotic disorder not otherwise specified) as defined in the DSM‐IV
Interventions	Location: USA, hospital sites in Columbus, Cincinnati, and Wichita Study duration: Not stated Treatment groups: 1. Valproate (VPA): initial dose of 10 mg/kg/day on a twice‐daily schedule beginning on day 0. VPA levels were adjusted to achieve a blood level of 80 – 100 µg/mL. The mean dose of VPA at endpoint was 300 mg/day. The mean level of VPA at study endpoint was 81 ± µg/mL 2. Risperidone: the mean dose of risperidone at endpoint was 0.5 mg/day (range 0.5 – 0.75 mg/day). Medications were administered in a double‐blind manner on a twice‐daily basis 3. Placebo: active medication and placebo were administered in liquid form matched for taste and colour Concomitant medications: the concurrent use of antipsychotics, antidepressants, and mood stabiliser/anticonvulsant medication other than the study drug was not allowed during study participation. The adjunctive use of oral chlorpromazine in low doses, 10 – 20 mg/day, 2 to 3 times a week, was allowed for sleep disturbance or agitation during the first 2 weeks of this trial Length of study: 6 weeks of intervention in addition to 3 ‐ 7 days screening period. There was a 1‐week washout period prior to study entry, except for those who took aripiprazole or fluoxetine who needed 4 weeks. Other psychotropic medication required 2 weeks Randomisation: 21 patients randomised to valproate 18 patients randomised to risperidone 7 patients randomised to placebo
Outcomes	Outcomes: 1. Change in YMRS scores from baseline 2. Change in CDRS‐R scores from baseline 3. Clinical Global Impression ‐ Bipolar Illness ‐ Severity Scale (CGI‐BP‐S) 4. Clinical Global Impression ‐ Bipolar Illness ‐ Improvement Scale (CGI‐BP‐I) Safety/Tolerability: Adverse events, changes in body measures (e.g., BMI) Study withdrawals were reported
Funding	"The Stanley Medical Research Foundation funded study was designed to test the efficacy of risperidone versus VPA in children and adolescents with symptomatic bipolar I or II disorder during a mixed, manic, or hypomanic episode."
Conflict of interest	"Dr. Kowatch is a consultant and faculty for the Resource for Advancing Children’s Health (REACH) Institute. He receives research support from the National Institute of Mental Health (NIMH). He is employed by Ohio State University and is an editor for Current Psychiatry. Drs. Scheffer, Monroe, Delgado, and Altaye, and Ms. Lagory disclosed no conflicts of interest."
Notes	Study focused on children between 3 and 7 years of age
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: Randomisation procedure not specified in text. We contacted the authors who informed that a random‐number generator was used to generate a random sequence.
Allocation concealment (selection bias)	Low risk	Comment: Procedures to conceal allocation not specified in text. We contacted the authors who informed us that the random sequences were stored in the pharmacy department and were only accessible to the pharmacy staff. Therefore, low risk of bias.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Active medication and placebo were administered in liquid form matched for taste and colour. Medication were administered in a double‐blinded manner on a twice daily basis." Quote: "An independent, unblinded study psychiatrist adjusted the VPA dosis to achieve a therapeutic level." Quote: "An unblinded study coordinator [...] coordinated dose increases with the unblinded medical monitor at each site." Comment: Blinding procedures seem robust.
Blinding of outcome assessment (detection bias) Efficacy	High risk	Quote: "Subjects were assessed weekly for efficacy during the acute phase by one of the site principal investigators, who was blind to medication status and adverse events (AEs)." Quote: "An unblinded study coordinator performed the weekly side‐effect ratings using the Side Effects Form for Children and Adolescents." Comment: Efficacy measures properly blinded. However, adverse events are not. Therefore, overall high risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: In all groups dropout rate was below 30%.
Selective reporting (reporting bias)	Low risk	Comment: Pre‐published protocol found. This protocol reports on all primary outcomes.
Other bias	Unclear risk	Comment: Chlorpromazine allowed as adjunctive medication but no comment on doses in either group is made and no comment on any group differences either.