Kushner 2006.

Methods	Study design: multicentre randomised, double‐ blind, placebo‐controlled, parallel‐group study
Participants	Diagnosis: acute manic or mixed episodes of bipolar I disorder. Method of diagnosis: "a primary DSM‐IV diagnosis of bipolar I disorder and hospitalised with an acute manic or mixed episode, confirmed by a SCID Axis I Disorders" Age: for lithium, median = 42 (SD = 13) years; for topiramate 200, median = 42 (SD = 14) years; for topiramate 400, median = 43 (SD = 14) years; for placebo, median = 43 (SD = 14) years Sex: lithium 49% women; 51% men, topiramate 200 55% women; 45% men, topiramate 400 46% women; 54% men, placebo 59% women; 41% men. Location: USA and 19 other countries (Eastern and Western Europe, Argentina, Australia, India, Israel, Latin America, South Africa) Co‐morbidities: not described Adjunctive therapy: none Adjunctive medication: "during the first 14 days of double‐blind treatment, chloral hydrate, non‐benzodiazepine short‐acting sedative hypnotics, and short‐acting benzodiazepine anxiolytics could be used as rescue medication. Patients requiring antipsychotics or mood stabilizers were discontinued. Non‐pharmacologic interventions other than supportive or educational psychotherapy were prohibited."
Interventions	Participants were randomly assigned to either: Experimental arm ‐ lithium Duration: 3 weeks (core study) Treatment protocol: "Each of the four studies included a screening phase during which previous psychotropic medications were discontinued, followed by randomisation to double‐blind treatment for 3 weeks (core study); in three studies, double‐blind treatment was continued for a total of 12 weeks (3‐week core study + 9‐ week double‐blind extension). Screening/washout. The screening‐phase duration varied according to the time needed for medication washout. A 48‐hour washout was allowed if YMRS score worsened by ‡25% compared with screening. Otherwise, the washout period was equivalent to five half‐lives of the medication in use or one treatment cycle for depot antipsychotic medications The washout period was extended for 1 week if YMRS score improved ≥ 25% from the screening score; if the patient’s YMRS score was ≥ 20 after the 2‐week washout, the patient could be randomised to double‐blind treatment. Randomization/titration. Patients eligible after washout were randomised to topiramate, placebo, or lithium. To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid‐day lithium dose to achieve target levels, with sham adjustments in the mid‐day (inactive) dose for participants in topiramate and placebo groups. In studies with 9‐week double‐blind extensions, placebo‐treated participants were crossed over to lithium (target: 1500 mg/day; PDMD‐004) or to topiramate (target: 150 mg/day; PDMD‐008). Dose titration and adjustments for lithium‐treated participants followed the same schedule as in the core double‐blind study. For participants converted to topiramate, the starting dose was 50 mg/day increased in 50 mg increments on days 2 and 3." Therapist/face‐to‐face contact: not described Comparator arm ‐ topiramate 200 Duration: 3 weeks (core study) Treatment protocol: "Each of the four studies included a screening phase during which previous psychotropic medications were discontinued, followed by randomization to double‐blind treatment for 3 weeks (core study); in three studies, double‐blind treatment was continued for a total of 12 weeks (3‐week core study + 9‐ week double‐blind extension). Screening/washout. The screening‐phase duration varied according to the time needed for medication washout. A 48‐h washout was allowed if YMRS score worsened by ≥ 25% compared with screening. Otherwise, the washout period was equivalent to five half‐lives of the medication in use or one treatment cycle for depot antipsychotic medications The washout period was extended for 1 week if YMRS score improved ≥ 25% from the screening score; if the patient’s YMRS score was ⪕ 20 after the 2‐week washout, the patient could be randomised to double‐blind treatment. Randomization/titration. Patients eligible after washout were randomised to topiramate, placebo, or lithium. The starting dose of 50 mg/day topiramate was increased to 100 mg/day at day 2 and in 100 mg increments each day for the next 1–5 days until the target dose (200, 400, or 600 mg/day) or the maximally tolerated dose was achieved. Investigators could slow titration by withholding doses or could reduce the dosage, with a maximum reduction of two tablets or capsules (100 mg/day topiramate) to improve tolerability To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid‐day lithium dose to achieve target levels, with sham adjustments in the mid‐day (inactive) dose for participants in topiramate and placebo groups. In studies with 9‐week double‐blind extensions, placebo‐treated participants were crossed over to lithium (target: 1500 mg/day; PDMD‐004) or to topiramate (target: 150 mg/day; PDMD‐008). Dose titration and adjustments for lithium‐treated participants followed the same schedule as in the core double‐blind study. For participants converted to topiramate, the starting dose was 50 mg/day increased in 50 mg increments on days 2 and 3." Therapist/face‐to‐face contact: not described Comparator arm ‐ topiramate 400 Duration: 3 weeks (core study) Treatment protocol: "Each of the four studies included a screening phase during which previous psychotropic medications were discontinued, followed by randomization to double‐blind treatment for 3 weeks (core study); in three studies, double‐blind treatment was continued for a total of 12 weeks (3‐week core study + 9‐ week double‐blind extension). Screening/washout. The screening‐phase duration varied according to the time needed for medication washout. A 48‐h washout was allowed if YMRS score worsened by ≥25% compared with screening. Otherwise, the washout period was equivalent to five half‐lives of the medication in use or one treatment cycle for depot antipsychotic medications The washout period was extended for 1 week if YMRS score improved ≥ 25% from the screening score; if the patient’s YMRS score was ≥ 20 after the 2‐week washout, the patient could be randomised to double‐blind treatment. Randomization/titration. Patients eligible after washout were randomised to topiramate, placebo, or lithium. The starting dose of 50 mg/day topiramate was increased to 100 mg/day at day 2 and in 100‐mg increments each day for the next 1–5 days until the target dose (200, 400, or 600 mg/day) or the maximally tolerated dose was achieved. Investigators could slow titration by withholding doses or could reduce the dosage, with a maximum reduction of two tablets or capsules (100 mg/day topiramate) to improve tolerability. To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid‐day lithium dose to achieve target levels, with sham adjustments in the mid‐day (inactive) dose for participants in topiramate and placebo groups. In studies with 9‐week double‐blind extensions, placebo‐treated participants were crossed over to lithium (target: 1500 mg/day; PDMD‐004) or to topiramate (target: 150 mg/day; PDMD‐008). Dose titration and adjustments for lithium‐treated participants followed the same schedule as in the core double‐blind study. For participants converted to topiramate, the starting dose was 50 mg/day increased in 50 mg increments on days 2 and 3." Therapist/face‐to‐face contact: not described Comparator arm ‐ placebo Duration: 3 weeks (core study) Treatment protocol: "Each of the four studies included a screening phase during which previous psychotropic medications were discontinued, followed by randomization to double‐blind treatment for 3 weeks (core study); in three studies, double‐blind treatment was continued for a total of 12 weeks (3‐week core study + 9‐ week double‐blind extension). Screening/washout. The screening‐phase duration varied according to the time needed for medication washout. A 48‐h washout was allowed if YMRS score worsened by ≥ 25% compared with screening. Otherwise, the washout period was equivalent to five half‐lives of the medication in use or one treatment cycle for depot antipsychotic medications The washout period was extended for 1 week if YMRS score improved ≥25% from the screening score; if the patient’s YMRS score was ≥ 20 after the 2‐week washout, the patient could be randomised to double‐blind treatment. Randomization/titration. Patients eligible after washout were randomised to topiramate, placebo, or lithium. In studies with lithium as an active comparator (PDMD‐004 and PDMD‐008), the starting dose of 300 mg/day lithium was increased daily in 300‐mg increments to 1200 mg/day at day 4 and 1500 mg/day at day 6; lithium dosage could be reduced a maximum of 600 mg/day. lithium dosage was individualized based on target serum levels (titration, 0.8–1.2 mEq/L; stabilization, 0.6– 1.2 mEq/L; maximum 1800 mg/day). To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid‐day lithium dose to achieve target levels, with sham adjustments in the mid‐day (inactive) dose for participants in topiramate and placebo groups. In studies with 9‐week double‐blind extensions, placebo‐treated participants were crossed over to lithium (target: 1500 mg/day; PDMD‐004) or to topiramate (target: 150 mg/day; PDMD‐008). Dose titration and adjustments for lithium‐treated participants followed the same schedule as in the core double‐blind study. For participants converted to topiramate, the starting dose was 50 mg/day increased in 50 mg increments on days 2 and 3." Therapist/face‐to‐face contact: not described Participants randomised in each part of the study: 004: placebo = 111, topiramate = 220, lithium = 113 008: placebo = 112, topiramate = 116, lithium = 114
Outcomes	Timepoints for assessment: 3 Weeks + 12 weeks Primary outcome: YMRS Secondary outcome: DSM‐IV defined responder Mania exacerbation ‐ YMRS increase ≥ 10% from baseline Treatment emergent depression (MADRS) Weight gain Withdrawal Adverse events
Notes	Date of study: not described Funding source: these studies were sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. SFK, AK and RL are employees of Johnson & Johnson Pharmaceutical Research & Development. WHO is an employee of Ortho‐McNeil Janssen Scientific Affairs, L.L.C. Declarations of interest among the primary researchers: none given
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias) All outcomes	Low risk	"Study treatment was blinded to participants, investigators and clinical staff, study monitors, data reviewers, and data entry personnel until the double‐blind phase was completed and the data‐ base was finalized. The central laboratory had access to the randomization code in order to identify blood samples for assaying lithium blood levels. To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid‐day lithium dose to achieve target levels, with sham adjustments in the mid‐day (inactive) dose for participants in topiramate and placebo groups. Topiramate and placebo were supplied as matching 50‐ or 100‐mg tablets (PDMD‐005 and PDMD‐006) or as identical‐appearing capsules (PDMD‐004 and PDMD‐008) that contained two 25‐mg topiramate tablets, placebo, or 300‐mg lithium capsules. Study treatment was blinded to participants, investigators and clinical staff, study monitors, data reviewers, and data entry personnel until the double‐blind phase was completed and the data‐ base was finalized."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not clearly described. ‘Premature discontinuations from the core studies plus double‐ blind extensions were related to adverse events in 7% of placebo‐treated participants, 4% with placebo/ topiramate, 8–11% with topiramate, 13% with lithium, and 13% with placebo/lithium.’
Selective reporting (reporting bias)	Unclear risk	Not clear if all data reported or not.
Other bias	Low risk	None identified