02. Bipolar Disorder Maintenance: What’s the Optimal Dose Range?

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Optimal Dosing for Bipolar Maintenance Treatment

As a clinician treating patients with bipolar disorder, I find the topic of real-world medication dosing for maintenance treatment particularly exciting. While helping patients recover from depressive or manic episodes is crucial, keeping them well is equally important and rewarding. In psychiatry, we often adhere to the adage “what gets them well keeps them well,” but is there data to support this approach?

Finnish Study Challenges Conventional Dosing

A nationwide Finnish study published in Acta Psychiatrica Scandinavica examined real-world patients over more than a decade, challenging some conventional thinking about medication dosing for bipolar disorder. The study suggests that higher doses of commonly prescribed medications don’t always lead to better long-term results.

Standard Doses: The Sweet Spot

The study investigated the relationship between different doses of antipsychotics and mood stabilizers and the likelihood of relapse, measured by psychiatric hospitalizations. For most medications examined, including:

• Olanzapine
• Risperidone
• Valproate
• Lamotrigine

Standard doses appeared to be the sweet spot, resulting in the lowest rates of psychiatric hospitalization. Interestingly, carbamazepine at a moderate 400 mg dose also showed lower relapse rates.

Aripiprazole: Promising Results

Aripiprazole demonstrated notably low relapse risk at both low and standard doses, outperforming other antipsychotics studied (olanzapine, quetiapine, and risperidone). This finding is particularly intriguing because, despite its modest efficacy for the treatment of bipolar depression, aripiprazole may exhibit superior outcomes in preventing overall relapse.

Quetiapine: Limited Maintenance Efficacy

Surprisingly, quetiapine, often prescribed for bipolar disorder and known for its efficacy in treating bipolar depression, didn’t show a reduction in relapse risk at any dosage in this study.

Safety Considerations: Non-Psychiatric Hospitalizations

The study also examined non-psychiatric hospitalizations as an indicator of potential medication side effects. Most antipsychotics were associated with increased risk of non-psychiatric hospitalizations at all dose ranges, especially at higher doses. The exception was aripiprazole at low or standard dosages, which was relatively neutral in this regard. Similarly, mood stabilizers at low to standard dosages presented neutral risk profiles.

Lithium: Dual Benefits Reaffirmed

Lithium, a mainstay in bipolar treatment, showed promising results:

• At low to moderate dosages, it was associated with decreased risk of non-psychiatric medical hospital admissions
• It was linked to decreased relapse risk at all dosages

This data reinforces lithium’s dual efficacy in treating mania and preventing relapse during the maintenance phase. This finding reframes lithium’s risk profile and challenges prevailing concerns about long-term renal and thyroid effects. Fortunately, these potential complications can be adequately detected through biannual laboratory monitoring.

Study Limitations: Considering Patient Factors

It’s crucial to acknowledge a major limitation of this real-world data: patients on higher medication dosages often have more severe forms of bipolar disorder or other psychiatric comorbidities. Their higher relapse rates may be due to inherently more difficult-to-treat conditions rather than medication dosage.

Practical Implications for Clinicians

Based on these findings, I recommend the following approach:

1. Get patients well at their individually effective dosage within the safe prescribing range.
2. Balance efficacy against emerging side effects as dosages increase.
3. After six months of remission, consider slowly tapering down to a moderate or low dose range.
4. For patients who improved on quetiapine, consider cross-titrating to a medication with better maintenance data, such as aripiprazole or lithium.
5. Consider lamotrigine as a maintenance drug to prevent bipolar depression episodes longer term, as it offers a favorable combination of effectiveness and tolerability.
6. Monitor patient response, mood stability, and side effects throughout the process.

Newer Medication Considerations

This study didn’t examine newer antipsychotics like lurasidone, cariprazine, and lumateperone. These medications have demonstrated efficacy in bipolar disorder and more favorable metabolic side effect profiles. Their impact on non-psychiatric hospitalizations remains to be seen.

Key Takeaways

• Standard doses are often the most effective and safest long-term option for bipolar medications
• Aripiprazole shows promise in preventing relapse
• Quetiapine’s long-term effectiveness may be limited
• Lithium continues to demonstrate benefits beyond mood stabilization
• Carbamazepine and lamotrigine are underutilized options for maintenance treatment

Approach medication dosing cautiously and with a personalized mindset, monitor closely for efficacy and side effects, and consider adjusting dosages downward during the maintenance phase as needed.

Abstract

Dosing levels of antipsychotics and mood stabilizers in bipolar disorder: A Nationwide cohort study on relapse risk and treatment safety

Jonne Lintunen, M.D., Aleksi Hamina, M.D., Markku Lähteenvuo, M.D., Tapio Paljärvi, M.D., Antti Tanskanen, M.D., Jari Tiihonen, M.D. & Heidi Taipale, M.D.

Background: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder.

Methods: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used.

Results: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88).

Conclusions: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose.

Keywords: adverse effects; antipsychotic agents; bipolar disorder; mood stabilizers; relapse.

Reference

Lintunen, J. M.D., Hamina, A. M.D., Lähteenvuo, M. M.D., Paljärvi, T. M.D., Tanskanen, A. M.D., Tiihonen, J. M.D. & Taipale, H. M.D. Dosing levels of antipsychotics and mood stabilizers in bipolar disorder: A Nationwide cohort study on relapse risk and treatment safety. (2025). Acta Psychiatrica Scandinavica 151(1):81-91.