Calabrese 2005.

Methods	Randomised double‐blind placebo‐controlled parallel‐group trial
Participants	60 participants Drug formulation: divalproex Age: mean age of 36 years Diagnosis: DSM‐IV Bipolar I or II disorder Inclusion criteria Rapid cycling disorder in the previous 12 months Hypomanic, manic or mixed episode in previous 3 months, in good physical health Exclusion criteria from maintenance phase Previous concurrent lithium and valproate treatment Intolerance Pregnancy or planned pregnancy Exogenous steroids Drug or alcohol misuse in the previous 6 months Suicidality Refractory affective episode in stabilisation phase afterward
Interventions	Open‐label stabilisation phase of between 12 and 24 weeks to stabilise and to establish treatment on concurrent valproate and lithium; all other psychotropic medications tapered off before randomisation Randomly assigned to monotherapy valproate or lithium under double‐blind conditions Doses adjusted to reach serum trough levels: minimum 0.8 mEq/L for lithium and 50 microgrammes/L for valproate, down‐titrated for side effects Rescue medication: unclear Duration of trial: 20 months
Outcomes	Study withdrawal due to episode of mood disorder Adverse events Withdrawal due to adverse events
Notes	None
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned". Probably done
Allocation concealment (selection bias)	Unclear risk	No information reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double‐blind, double‐substitution methodology was used to transition patients from open‐label combination therapy with both medications to double‐blind monotherapy. Patients were started on equal numbers of capsules of double‐blind active lithium 300‐mg capsules and matching (in colour, taste, and size) lithium placebo capsules, and equal numbers of double‐blind active valproate in 250‐mg capsules and matching valproate placebo capsules.... Patients randomly assigned to monotherapy had one blinded active capsule replaced with a matching placebo capsule once every 2 weeks for as long as necessary. The process of tapering to monotherapy took place over an average of 6 weeks if patients were taking 1200 mg of lithium or 1500 mg of valproate—longer if the doses of either were higher and more quickly if the doses of either were lower. After the taper was completed, matching placebo for the drug that was discontinued was discontinued for the rest of the maintenance phase. This slow, gradual process of transitioning patients to monotherapy obscured the progress of the taper until completed. The maintenance phase began at the beginning of the taper, and the survival analysis began at that time as well. After the taper was completed, the number of capsules of active compound and placebo was unchanged for the rest of the maintenance phase, except for adjustments made to both by the unblinded medical monitor when blood levels decreased to less than 0.8 meq/liter for lithium and 50 μg/mL for valproate"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The intent‐to‐treat population included all patients who were randomly assigned to a study treatment condition. Kaplan‐Meier methodology was used to plot the survival data, and median survival times were calculated. A log‐rank test at an alpha = 0.05 level of significance was employed to evaluate differences between survival curves. A Cox regression was performed evaluating the following predictors of outcome: treatment arm assignment, type of bipolar diagnosis (bipolar I or bipolar II), and index episode at study entry"
Selective reporting (reporting bias)	Unclear risk	Study protocol not available
Other bias	Low risk	None