Chengappa 2006.

Methods	DESIGN Description: randomised, double‐blind, placebo‐controlled, parallel‐group, multicentre trial. Study visits occurred weekly during an 8‐week titration period and then biweekly for the remaining 4 weeks. BLINDING Participants: yes Assessors: yes Administrators: yes ALLOCATION CONCEALMENT Method: study medication was packaged by the sponsor according to the randomisation schedule and provided to the study sites with identification numbers RANDOMISATION: Method: a computer‐generated randomisation schedule was prepared before the study and was balanced using randomly permuted blocks
Participants	SAMPLE Description: 287 adult outpatients with bipolar 1 disorder (DSM‐IV criteria) experiencing a manic or a mixed episode with a YMRS score of ≥ 18 while taking therapeutic levels of valproate or lithium. Participants were required to have received either lithium or valproate for 6 weeks or more including a stable dose during the 2 weeks before the screening visit. Serum levels of mood stabiliser at the screening visit were required to be between 0.5 and 1.2 mEq/L for lithium or between 45 and 100 mg/L for valproate when drawn 8 to 12 hours after the last dose. Male and female adults aged between 18 and 70 years. Exclusion criteria included substance abuse or dependence (except alcohol or marijuana) in the previous 3 months; mania requiring hospitalisation; an organic mental disorder; mental retardation or a developmental disability; treatment‐emergent mania due to antidepressant use; use of an antidepressant or stimulant within the previous 2 weeks (4 weeks for fluoxetine) unless the antidepressant was given at a subtherapeutic dose; use of carbamazepine within the previous 2 weeks or another anticonvulsant within the previous 3 weeks; initiation of nutraceutical treatment (e.g. St John's wort) within the previous 4 weeks; long‐acting antipsychotic medication or oral antipsychotic medicine that was given above the maximum recommended dose or was not given at a stable dose during the previous 4 weeks; use of opiates or barbiturates within the previous 3 months; any clinically unstable comorbid disease; liver disease; untreated hypothyroidism; history of nephrolithiasis, seizures, or any contraindication or precaution that would preclude use of topiramate; and pregnancy, lactation, or inadequate contraception in women. SCREENING Primary diagnosis: SCID
Interventions	Interventions: 143 participants received adjunctive topiramate (titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks), and 144 participants received placebo, while taking therapeutic levels of valproate or lithium, for 12 weeks. The initial dose of topiramate was 25 mg once daily. The total daily dose was then titrated at weekly study visits, using the following sequence and a twice‐daily dosing schedule: 50, 75, 100, 150, 200, 300, and 400 mg. The investigator could stop titrating study medication due to adverse events, but the minimum allowed dose after the first week was 50 mg daily. After the 8‐week titration period, the same dose was continued for the remaining 4 weeks
Outcomes	Primary outcomes: measure was the change in YMRS score from baseline to last study visit during the double‐blind phase. YMRS ratings were assessed during screening and then at every visit during the double‐blind phase. Secondary outcomes: efficacy assessments were measured at screening and baseline (day 1) and then biweekly and included the CGI‐S, BPRS, MADRS, and GAS. Adverse events were reported at every visit. Data estimation: SAS version 9.1 was used for statistical analyses. Efficacy analyses were performed in the ITT population of participants who received at least 1 dose of study medication and completed at least 1 postbaseline assessment. Missing efficacy data were imputed with LOCF
Notes	INDUSTRY SUPPORT Industry funded: this study was supported by Ortho‐McNeil Neurologics, Inc. Medication provided by industry: yes Any of the authors work for industry: yes ADDITIONAL INFORMATION The study was conducted from October 2001 through October 2003. In addition to study medication and a stable dose of divalproex sodium or lithium, participants were permitted to continue taking a stable dose of an oral antipsychotic agent. The use of a short‐acting benzodiazepine (lorazepam) for sleep or agitation was permitted only during the first 4 weeks of the titration period. 49 participants (26 topiramate treated and 23 placebo treated) were included in the ITT population for efficacy analysis despite violating the study protocol by starting lithium or valproate fewer than 6 weeks before the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomisation schedule was prepared before the study and was balanced using randomly permuted blocks
Allocation concealment (selection bias)	Unclear risk	No information available to make judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	Figure 1 summarises the numbers screened, randomised, intent to treat, and discontinued with reasons. Both efficacy and safety analyses included all randomised participants with a least 1 postbaseline data
Selective reporting (reporting bias)	Low risk	All expected outcomes in terms of efficacy and safety are reported. All the study's prespecified primary outcomes are reported
Other bias	Unclear risk	The study was industry funded