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Lithium Plus Valproate Combination versus Monotherapy for Relapse Prevention in Bipolar I Disorder (BALANCE) 

Lithium Plus Valproate Combination versus Monotherapy for Relapse Prevention in Bipolar I Disorder (BALANCE)
Lithium Plus Valproate Combination versus Monotherapy for Relapse Prevention in Bipolar I Disorder (BALANCE)

João Paulo De Aquino

, and Robert Beech

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Subscriber: null; date: 23 October 2019

Our results suggest that patients should be advised that a better outcome would be likely with combination therapy with lithium plus valproate semisodium or lithium alone.

The BALANCE Investigators1

Research Question:

Is lithium plus valproate better than monotherapy with either drug alone for relapse prevention in bipolar I disorder?


Stanley Medical Research Institute; Sanofi Aventis

Year Study Began:


Year Study Published:


Study Location:

41 sites in the United Kingdom, United States, Italy, and France

Who Was Studied:

Patient aged 16 and older with a DSM-IV diagnosis of bipolar I disorder who required long term drug therapy to prevent relapse

Who Was Excluded:

Patients who were having an acute episode or had a medical disorder that precluded use of either lithium or valproate

How Many Participants:


Study Overview:

See Figure 3.1 for a summary of the study design.

Study Intervention:

First, there was a “run-in phase” of four to eight weeks where patients were given short-term trials of both medications to assess tolerability. Lithium was titrated to serum levels of 0.4 and 1 mmol/L, and valproate was given up to a target dose of 1,250 mg daily, or the highest tolerated dose. Those patients who had therapeutic lithium levels, valproate dose of at least 750 mg daily or concentration of 50 ug/mL, and were 70% compliant on medications were allowed to participate in the study phase.

In the study phase, patients were randomized in an open-label fashion to receive either medication as monotherapy or a combination of lithium and valproate.


24 months


The primary outcome was whether or not patients required a new intervention for an emergent mood episode. New interventions included adding or increasing medication dose or admission to the hospital. Secondary outcomes included global assessment of functioning, deliberate self-harm, quality of life, adverse events, and adherence to the assigned treatment.


  • The hazard ratio of the primary outcome (the need to start a new intervention to address a mood disturbance) was significantly lower in the participants allocated to combination therapy compared to those allocated to valproate monotherapy but not those allocated to lithium monotherapy.

  • The hazard ratio of the primary outcome was significantly lower in the group allocated to lithium monotherapy compared to those on valproate monotherapy.

  • The risk for hospital admission was lower for participants allocated to combination therapy compared to patients allocated to valproate monotherapy but was not significantly lower for those on lithium alone.

  • Discontinuation of allocated treatment, self-harm, quality of life, and global functioning did not differ significantly between groups (Table 3.1).

Table 3.1 Summary of BALANCE Trial’s Key Findings


Combination therapy

Lithium monotherapy

P value

Valproate monotherapy

P value

% with an emergent mood episode






Hazard ratio vs. combination therapy






Hazard ratio vs. lithium monotherapy



Criticism and Limitations:

Treatment allocation was not blinded from the investigators or participants. Therefore, performance and ascertainment biases could have arisen if clinicians or participants had behaved systematically differently dependent on the treatment allocation. Furthermore, around 21% of patients withdrew from the trial, although the reasons for withdrawal did not differ significantly between groups.

It is worthy of mention that the dose of valproate used was lower than is recommended for treatment of acute mania (1,200–1,500 mg/day), and increased doses might have improved its effectiveness. Finally, there was no placebo comparator group in this trial.

Other Relevant Studies and Information:

  • A previous smaller randomized trial compared lithium monotherapy with a combination of lithium plus valproate in patients with rapid cycling disorder and comorbid substance abuse.2 The estimate of the hazard ratio was in favor of combination therapy similar and to that recorded on BALANCE.1

  • There have been other studies investigating differences between lithium and valproate in the treatment of bipolar disorder,2,3 which found mixed results favoring the use of lithium over valproate in bipolar disorder.

  • According to the American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Bipolar Disorder, Second Edition,4 the medications with the best empirical evidence to support their use in maintenance phase include lithium and valproate, although this study supports efficacy of lithium over valproate as monotherapy. Alternatives include lamotrigine, carbamazepine, antipsychotics, or oxcarbazepine.

Summary and Implications:

The BALANCE trial was a landmark study that found that combination of lithium and valproate was not substantially superior to lithium alone in the treatment of bipolar disorder. The study did find some benefit of using lithium in combination with valproate, compared with valproate alone. Based on the results of this and other trials on this topic, the APA recommends using lithium and valproate as prophylactic treatment for episodic mood disturbances in people with bipolar disorder.

Clinical Case: Lithium Plus Valproate Versus Monotherapy in The Maintenance Treatment of Bipolar I Disorder

Case History

A 32-year-old woman with bipolar I disorder has been relatively stable for 3 months on valproate but over the last week has been irritable and agitated around the house and at work. She is uncertain about switching or optimizing the mood stabilizer would be the best course of action in her treatment.

Based on the results of BALANCE trial, how should this patient be treated?

Suggested Answer

The BALANCE trial found that combination of lithium and valproate is superior to valproate alone, but not lithium alone, in the maintenance treatment of bipolar disorder.

When planning long‐term pharmacological interventions to prevent relapse, physicians should take into account drugs that have been effective during manic or depressive episodes, discussing with the person the possible benefits and risks of each drug for them. A thorough discussion with the patient should follow aiming to clarify whether the patient prefers to continue this treatment or switch to lithium, as lithium is the most effective long‐term treatment for bipolar affective disorder. If lithium is insufficiently effective, consider adding valproate; if lithium not well tolerated, consider valproate or olanzapine as alternatives. If it has been effective during an episode of mania or bipolar depression, consider quetiapine. Valproate should be used carefully in women of child‐bearing age due to the risk of teratogenicity. Before stopping medication, a careful discussion with the patient on how to recognize early signs of relapse and what to do if symptoms recur is necessary.


1. Geddes, J. R., Goodwin, G.M., Rendell, J., Azorin, J.M., Cipriani, A., . . . Juszczak, E. (2010). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. Lancet, 375(9712), 385–395.Find this resource:

2. Calabrese, J. R., Shelton, M. D., Rapport, D. J., Youngstrom, E. A., Jackson, K., Bilali, S., . . . & Findling, R. L. (2005). A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. American Journal of Psychiatry, 162(11), 2152–2161.Find this resource:

3. Oquendo, M. A., Galfalvy, H. C., Currier, D., Grunebaum, M. F., Sher, L., Sullivan, G. M., . . . & Mann, J. J. (2011). Treatment of suicide attempters with bipolar disorder: A randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. American Journal of Psychiatry, 168(10), 1050–1056.Find this resource:

4. Hirschfeld, R. M., Bowden, C. L., Gitlin, M. J., Keck, P. E., Suppes, T., Thase, M. E., . . . Perlis, R. H. (2010). Practice guideline for the treatment of patients with bipolar disorder (2nd ed.). Washington, DC: American Psychiatric Association.Find this resource: