4 research outputs found
Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial
Background Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of
relapse in bipolar disorder, but are not individually fully eff ective in many patients. If combination therapy with both
agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish
whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I
disorder.
Methods 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy
were randomly allocated to open-label lithium monotherapy (plasma concentration 0·4–1·0 mmol/L, n=110), valproate
monotherapy (750–1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4–8 weeks on the
combination. Randomisation was by computer program, and investigators and participants were informed of
treatment allocation. All outcome events were considered by the trial management team, who were masked to
treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of
new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis
was by intention to treat. This study is registered, number ISRCTN 55261332.
Findings 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%)
of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome
were 0·59 (95% CI 0·42–0·83, p=0·0023) for combination therapy versus valproate, 0·82 (0·58–1·17, p=0·27) for
combination therapy versus lithium, and 0·71 (0·51–1·00, p=0·0472) for lithium versus valproate. 16 participants had
serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); fi ve lithium
monotherapy (two deaths); and four combination therapy (one death).
Interpretation For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination
therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate
monotherapy. This benefi t seems to be irrespective of baseline severity of illness and is maintained for up to 2 years.
BALANCE could neither reliably confi rm nor refute a benefi t of combination therapy compared with lithium
monotherapy