What is the therapeutic end point of valproate (valproic acid) in patients with bipolar disorder?

From the Guidelines

The therapeutic endpoint of valproate in patients with bipolar disorder is typically a serum concentration of 50-125 μg/mL, with most patients responding well within the 75-100 μg/mL range, and maintenance treatment should continue for at least 2 years after the last episode of bipolar disorder, as recommended by the WHO guidelines 1.

Key Considerations

• Dosing usually starts at 250-500 mg twice daily and is gradually titrated based on clinical response and serum levels, with most patients requiring 1000-2000 mg daily in divided doses.
• Blood level monitoring should be performed 12 hours after the last dose, with initial levels checked after 3-5 days of consistent dosing, and then periodically to ensure therapeutic concentrations are maintained.
• Clinical endpoints include stabilization of mood, reduction in manic or hypomanic symptoms, prevention of mood episodes, and improved overall functioning.
• Treatment response should be assessed through symptom reduction, functional improvement, and side effect monitoring.
• Regular liver function tests, complete blood counts, and monitoring for adverse effects such as sedation, tremor, gastrointestinal disturbances, and weight gain are essential components of valproate therapy management in bipolar disorder.

Maintenance Treatment

• Maintenance treatment with valproate or lithium should be continued for at least 2 years after the last episode of bipolar disorder, as recommended by the WHO guidelines 1.
• The decision to continue maintenance treatment after 2 years should preferably be done by a mental health specialist.
• The benefits and risks of continued treatment should be weighed on a case-by-case basis, considering the potential deleterious impact of symptom reoccurrence versus the side effects of the medications, as suggested by the practice parameter for the assessment and treatment of children and adolescents with bipolar disorder 1.

From the FDA Drug Label

The therapeutic range is commonly considered to be 50 to 100 μg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations The therapeutic end point of valproate in patients with bipolar disorder is not explicitly stated in the provided drug labels. However, based on the information provided for epilepsy, the therapeutic range is commonly considered to be 50 to 100 μg/mL of total valproate.

• It is essential to note that this range may not be directly applicable to bipolar disorder, as the provided drug labels primarily discuss epilepsy.
• The optimal clinical response is often achieved at daily doses below 60 mg/kg/day 2.
• Plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range if satisfactory clinical response has not been achieved 2.

From the Research

Therapeutic End Point of Valproate in Patients with Bipolar Disorder

The therapeutic end point of valproate in patients with bipolar disorder is to achieve mood stabilization and prevent episodes of mania or depression.

• Valproate is effective in the treatment of mania, particularly in patients with mixed mania or mania with prominent irritability 3.
• It is also effective in preventing new episodes of bipolar disorder, with similar efficacy to lithium and antipsychotics such as olanzapine and quetiapine 4.
• The optimal serum levels of valproate for therapeutic effect are not well established, but higher levels (above 110 microg/ml) may be associated with increased side effects such as weight gain, sedation, and reductions in platelet count 3.

Efficacy of Valproate in Maintenance Treatment

Valproate is effective in the maintenance treatment of bipolar disorder, with similar efficacy to lithium and antipsychotics.

• A systematic review and meta-analysis found that valproate was superior to placebo in preventing new episodes of bipolar disorder, and had similar efficacy to lithium and antipsychotics 4.
• Another study found that valproate was more effective than placebo in preventing study withdrawal due to any mood episode, but had similar efficacy to lithium 5.
• A post-hoc analysis of a randomized double-blind placebo-controlled trial found no significant differences in efficacy between valproate and lithium in the maintenance treatment of bipolar I disorder 6.

Factors Associated with Favorable or Unfavorable Outcomes

Several factors are associated with favorable or unfavorable outcomes in patients with bipolar disorder treated with valproate.

• Higher serum levels of valproate (above 110 microg/ml) may be associated with increased side effects such as weight gain, sedation, and reductions in platelet count 3.
• Combination therapy with lithium plus valproate may be more effective than monotherapy with valproate in preventing relapse 5.
• Valproate may be associated with an increased risk of polycystic ovarian syndrome, particularly in patients with weight gain 3.