Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:
- When should I measure serum valproate in bipolar patients?
- What do serum valproate levels mean in their clinical care?
To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.
Is monitoring overused?
Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes3 supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.
On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:
- acutely manic patients
- outpatients
- the elderly
- patients who are hypomanic or euthymic.4
Table 1
4 situations where serum valproate monitoring may be clinically useful
| To establish a baseline effective level in individual patients |
| To assess lack or loss of efficacy, including patient adherence |
| When drug-drug interactions increase or decrease valproate clearance (such as with aspirin, carbamazepine, felbamate, or phenytoin)5 |
| When dose-dependent side effects occur (such as alopecia, elevated liver function, thrombocytopenia, or pancreatitis) |
Effective levels in acute mania
In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al6 used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.
Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.
Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al7 compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.
Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.
The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.8 At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).
This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.
Optimum serum ranges. Allen et al9 recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:
- ≤55 mcg/mL (n=35)
- >55 to 71.3 mcg/mL (n=32)
- >71.3 to 85 mcg/mL (n=36)
- >85 to 94 mcg/mL (n=34)
- >94 to 107 mcg/mL (n=33)
- >107 mcg/mL (n=33).