Geller 2012.

Methods	Randomised single‐blind trial
Participants	Number of total participants/type of patients: 290 participants randomised. Outpatient study Inclusion criteria: Sex: male and female Age: children and adolescents (6 ‐ 15 years) Diagnosis: DSM‐IV diagnosis of bipolar I disorder, manic or mixed episode, for at least 4 consecutive weeks immediately preceding baseline, with a CGAS score of 60 or less at baseline and in good physical health. Co‐occurring attention‐deficit hyperactivity, oppositional defiant, and conduct disorder were allowed because these are common comorbidities in childhood mania. Suicidal ideation was allowed if there was no imminent risk. Participants required no history of receiving study psychotropics or their equivalents. All medication histories were verified by physician or pharmacy records, or both, to enhance interview accuracy. Exclusion criteria: An IQ of less than 70, a lifetime history of schizophrenia, pervasive developmental disorder or major medical or neurological disease, substance use dependency, alcohol or drug abuse within the past 4 weeks, pregnancy, sexually active and not using contraceptives, or nursing. Other psychotropics and medications associated with psychiatric symptoms were not permitted.
Interventions	Location: USA, hospital sites in Washington DC, Baltimore, Pittsburgh, Dallas, and St. Louis Study duration: 2003‐2008 Treatment groups: Valproate: started at 125 mg or 250 mg (depending on participant's weight) for 2 days, then 125/250 mg twice a day. This dose was adjusted based on the participant's reaction to up to 111 ‐ 135 µg/ml Risperidone: started at 0.25 mg or 0.5 mg for 2 days (depending on participant's weight), then 0.5 mg twice a day. This dose was adjusted based on the participant's reaction to up to 2.0 ‐ 3.0 mEq/L Lithium: started at 150 mg or 300 mg (depending on participant's weight) for 2 days, then 150/300 mg twice a day. This dose was adjusted based on the participant's reaction to up to 1.1 ‐ 1.3 mEq/L Concomitant medications: Maintenance methylphenidate and amphetamine preparations (total daily dose equivalent to < 60 mg methylphenidate), verified by pharmacy/physician records, and allergy/asthma medications were allowed, to mimic usual clinical practice. No stimulant dose adjustment was allowed during protocol. Antidepressants were tapered during the first week of study to avoid risk of increased mania symptoms. Participants required no history of receiving study psychotropics or their equivalents. All medication histories were verified by physician or pharmacy records, or both, to enhance interview accuracy Length of study: 8 weeks Randomisation: Randomisation was stratified by age group. 104 patients randomised to valproate 93 patients randomised to risperidone 93 patients randomised to lithium
Outcomes	Primary outcome: CGI‐BP‐I. Secondary outcome: K‐SADS Mania Rating Scale (KMRS). Adverse events were reported. Study withdrawals were reported.
Funding	"This work was supported by the National Institute of Mental Health"
Conflict of interest	"Dr Geller reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; payment for writing or reviewing the manuscript from NIMH; and provision of writing assistance, equipment, or administrative support from NIMH. Dr Geller also reports the following from outside the submitted work: consultancy for NIMH and the US Food and Drug Administration (FDA) Federal Advisory Committees; employment at Washington University in St Louis, Missouri; grants from NIMH; payment for lectures from Vanderbilt University and the International Review of Bipolar Disorder; payment for manuscript preparation from NIMH; royalties from Guilford Press; travel, accommodations, and meeting expenses from NIMH and FDA for service on Federal Advisory Committees; payment from Massachusetts Medical Society for Journal Watch in Psychiatry Associate Editorship. Dr Luby reports the following for the work under consideration: grant from NIMH and provision of medicines from Abbott. Dr Luby also reports the following from outside the submitted work: employment at Washington University School of Medicine in St Louis, Missouri; grants/grants pending fromNIMH, National Alliance for Research on Schizophrenia and Depression, and CHADS; and royalties from Guilford Press. Dr Joshi reports the following from the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; provision of medicines from Abbott. Dr Joshi also reports the following from outside the submitted work: employment at Children’s National Medical Center in Washington, DC. Dr Wagner reports the following from the work under consideration: grant from NIMH and provision of medicines from Abbott. Dr Wagner also reports the following from outside the submitted work: consultancy for Forest, American Institute of BiologicalSciences, Krog and Partners, and National Institutes of Health; employment at University of Texas Medical Branch in Galveston; payment for lectures from American Psychiatric Association, Letters and Sciences, American Society of Clinical Psychopharmacology, Toledo Hospital, American Academy of Child and Adolescent Psychiatry, Madison Institute of Medicine, Mexican Psychiatric Association, Contemporary Forums, Doctors Hospital at Renaissance, CME LLC, Nevada Psychiatric Association, and Quantia Communications; payment for manuscript preparation from Guilford Publications, Health and Wellness Education Partners, American Psychiatric Publishing Inc, Springer Publishing, CMP Medica, UBM Medica, and Wolters Kluver Health; payment from Physician’s Postgraduate Press, Inc, for serving as deputy editor of the Journal of Clinical Psychiatry. Dr Wagner also sits on the Scientific Advisory Board of the Child and Adolescent Bipolar Foundation and on the Scientific Advisory Board of the Depression and Bipolar Support Alliance. Dr Emslie reports the following from the work under consideration: a grant from NIMH and provision of medicines from Abbott. Dr Emslie also reports the following from outside the submitted work: consultancy for Biobehavioral Diagnostics, Inc, Eli Lilly, Forest, GlaxoSmithKline, Pfizer, Shire, Validus, and Wyeth; employment at University of Texas Southwestern Medical Center; grants/grants pending from NIMH, Biobehavioral Diagnostics, Inc, Eli Lilly, Forest, GlaxoSmithKline, Shire, and Somerset; payment for lectures, including service on speakers bureaus from Forest; and receiving payment for manuscript preparation from British Medical Journal Online. Dr Walkup reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Axelson reports the following for the work under consideration: a grant from NIMH. Ms Bolhofner reports the following for the work under consideration: a grant from NIMH. Ms Bolhofner also reports the following from outside the submitted work: employment at Washington University in St Louis, Missouri, and grants from NIMH. Dr Robb reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; provision of medicines from Abbott; and payment for serving as clinical pharmacologist for the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Robb also reports the following from outside the submitted work: board membership at Lilly, Bristol Myers Squibb, Otsuka, Shinogi, and McNeil Pediatrics; consultancy for Lundbeck; employment at Children’s National Medical Center; expert testimony for a case on antipsychotic use; grants/grants pending from Bristol Meyers Squibb, McNeil Pediatrics, Merck Scherring Plough, GlaxoSmithKline, Janssen, Sepracor, Supernus, Otsuka, Pfizer, Johnson and Johnson, and Forest; payment for service on speakers bureaus from Bristol Myers Squibb, Lilly, and McNeil Pediatrics; royalties from Epocrates; payment for development of education presentations from University of Minnesota, American Academy of Child& Adolescent Psychiatry, and American Academy of Pediatrics; stock/stock options from Lilly, Pfizer, Johnson and Johnson, GlaxoSmithKline, and 3M. Dr Robb also sits on the Children and Adults with Attention‐Deficit/Hyperactivity Disorder professional advisory board and program committee for the American Psychiatric Association annual meeting, and her husband sits on American Epilepsy Society Board and Scientific Committee for Child Neurology Society. Dr Wolf reports the following for the work under consideration: a grant from NIMH. Dr Riddle reports the following for the work under consideration: a grant from NIMH and provision of medicines from Abbott. Dr Riddle also reports the following from outside the submitted work: employment at Johns Hopkins University; expert testimony for Teva Canada; and receiving aripiprazole for an NIMH study. Dr Birmaher reports the following for the work under consideration: a grant from NIMH. Dr Birmaher also reports the following from outside the submitted work: consultancy for Schering Plough, Dey Pharma, Forest, and Jazz Pharmaceuticals; and royalties from Random House and Lippincott Williams and Wilkins. Dr Nusrat reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Nusrat also reports the following from outside the submitted work: employment at Children’s National Medical Center and grants/grants pending from Merck/Scherring Plough, GlaxoSmithKline, Janssen, Sepracor, Supernus, Otsuka, Pfizer, Johnson and Johnson, and Forest. Dr Ryan reports the following for the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; and provision of medicines from Abbott. Dr Ryan also reports the following from outside the submitted work: employment at the University of Pittsburgh and the University of Pittsburgh Medical Center. Ms Tillman reports the following for the work under consideration: a grant from NIMH and payment for writing or reviewing the manuscript from NIMH. Ms Tillman also reports the following from outside the submitted work: employment at Washington University in St Louis and receiving travel/accommodations/meeting expenses from NIMH. Dr Lavori reports the following for the work under consideration: a grant from NIMH."
Notes	Study focused on children/teenagers between 6 – 15.11 years of age.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The ranuni function in the SAS version 8.1 statistical software package (SAS Institute Inc) was used to create random lists of the 3 medications for each combination of the stratifying variables at each site."
Allocation concealment (selection bias)	Low risk	Quote: "When subjects were randomly assigned, the randomised medication was determined by selecting the next available entry in the list corresponding to the subject’s stratifying variables and site. Randomization was performed at the coordinating site, and a form identifying the randomised medication was e‐mailed to the site’s non‐blinded staff members.”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Patients, family members, and treating clinicians were aware of treatment assignment."
Blinding of outcome assessment (detection bias) Efficacy	Low risk	Quote: "Independent evaluators (IEs) who were blinded to medication status administered baseline and endpoint assessments.Masking of the treatment assignment to the IEs was strictly enforced by using staff who were totally uninvolved with the subjects’ treatment. Families were instructed not to reveal either the medication or adverse events to the blinded end‐point raters.Separate,non‐blinded interviewers conducted the weekly assessments." Comment: Baseline and endpoint measures are our primary outcome, and these are low risk. Midpoint scores are high risk, as raters were not blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "The discontinuation rate was significantly higher for subjects randomly assigned to the lithium group than for subjects randomly assigned to the risperidone group (32.2 % vs 15.5%)." Comment: Dropout rates above 30% in at least 1 group. Rates two‐fold higher in lithium group compared to risperidone.
Selective reporting (reporting bias)	High risk	Quote: "Adverse effects were considered present if the severity score was a 2 or 3 on a scale of 0 to 3. The only adverse effects presented are those that occurred in at least 5% of subjects who were treated with the given medication and that had at least a twofold increase or decrease during the study" Comment: Efficacy outcomes reported in line with pre‐published protocol. Comment: Adverse events reported in a way that makes analysis of the data impossible. We contacted the authors to ask for a full list of experienced side effects but they did not reply.
Other bias	Low risk	Comment: None identified.