Introduction

Bipolar disorder is a chronic mental health condition marked by episodes of mania, hypomania, and depression. Long-term treatment is essential to prevent relapses, reduce hospitalizations, and improve quality of life. For decades, psychiatrists have relied on mood stabilizers like lithium and valproate, but the question remained: Which works best for long-term maintenance?

The landmark BALANCE study (Bipolar Affective disorder: Lithium/ANtiConvulsant Evaluation), published in The Lancet (2010), addressed this critical clinical question.

What Was the BALANCE Study?

The BALANCE study was a large, pragmatic randomized controlled trial designed to compare three maintenance strategies in bipolar I disorder:

1. Lithium monotherapy

2. Valproate monotherapy

3. Lithium + Valproate combination therapy

The study enrolled over 300 adults across multiple centers, making it one of the most significant head-to-head evaluations of mood stabilizers in real-world settings.

Key Findings

1. Lithium Outperformed Valproate

Patients on lithium—either alone or in combination—were less likely to relapse compared to those on valproate monotherapy. Lithium proved especially protective against manic relapses.

2. Combination Therapy Was Effective

The lithium + valproate combination had the lowest relapse rates overall. However, the difference compared to lithium alone was modest, suggesting that lithium monotherapy remains sufficient for many patients.

3. Valproate Alone Was Less Effective

Valproate monotherapy was consistently associated with higher relapse rates, highlighting its limitations as a sole maintenance option.

4. Tolerability and Side Effects

Adverse effects were similar across groups. As expected, combination therapy meant a higher pill burden, but no unexpected safety issues emerged.

Clinical Implications

The BALANCE trial reshaped maintenance treatment strategies for bipolar disorder:

• Lithium remains the gold standard for long-term relapse prevention.

• Valproate should not be used as first-line monotherapy in maintenance unless lithium is contraindicated or poorly tolerated.

• Combination therapy (lithium + valproate) may be considered in patients with frequent relapses or mixed features.

• Lithium’s anti-suicidal benefits further strengthen its role as the cornerstone of bipolar treatment.

Why the BALANCE Study Matters

The BALANCE study is unique because it:

• Directly compared two of the most widely prescribed mood stabilizers.

• Used a pragmatic, real-world design instead of highly selective clinical trial samples.

• Provided strong evidence that helps clinicians and patients make evidence-based, personalized choices in bipolar disorder care.

Conclusion

The BALANCE study remains one of the most influential trials in bipolar disorder treatment. Its clear message is that lithium—alone or with valproate—provides superior protection against relapse compared to valproate alone. For clinicians, this reinforces lithium’s status as the first-line choice for maintenance therapy in bipolar I disorder.

As psychiatry continues to evolve, the BALANCE trial serves as a reminder that rigorous comparative studies are essential to guide long-term treatment strategies for complex conditions like bipolar disorder.

About the Author

✦ Dr. Srinivas Rajkumar T, MD (AIIMS, New Delhi), DNB, MBA (BITS Pilani)
Consultant Psychiatrist, Mind and Memory Clinic, Apollo Clinic, Velachery, Chennai (Opp. Phoenix Mall)

I specialize in bipolar disorder, ADHD, neuromodulation therapies, and digital psychiatry. My work integrates clinical practice with cutting-edge research to bring patients objective, effective, and personalized care.

📧 srinivasaiims@gmail.com
📞 +91 85951 55808