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 effective 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.


RESULTS
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); five lithium monotherapy (two deaths); and four combination therapy (one death).


CONCLUSIONS
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 benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.


BACKGROUND
Stanley Medical Research Institute; Sanofi-Aventis.
Oxford Clinical Trials Unit for Mental Illness, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK. john.geddes@psych.ox.ac.uk
Geddes
John R
JR
Goodwin
Guy M
GM
Rendell
Jennifer
J
Azorin
Jean-Michel
JM
Cipriani
Andrea
A
Ostacher
Michael J
MJ
Morriss
Richard
R
Alder
Nicola
N
Juszczak
Ed
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D018692:Antimanic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016651:Lithium Carbonate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D055502:Secondary Prevention; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use*; D055815:Young Adult
D018692:Antimanic Agents; D016651:Lithium Carbonate; D014635:Valproic Acid