Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.
Keck et al10 examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.
Hirschfeld et al11 also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).
Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.
Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.
In maintenance therapy
What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.
Bowden et al12 compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.
Thirteen subjects in the divalproex group were then stratified into 4 categories:
- nontherapeutic (
- low therapeutic (50 to 74.9 mcg/mL)
- medium therapeutic (75 to 99.9 mcg/mL)
- high therapeutic (>100 mcg/mL).
Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.
In bipolar depression
Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.
In an 8-week, double-blind study, Davis et al14 randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.
Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.
Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).16
2 tips for reliable serum valproate monitoring
When evaluating serum valproate levels–especially for assessing adherence–be careful to:
- obtain blood samples 12 hours after the most recent dose to accurately assess serum trough concentrations
- account for valproate’s saturation of protein binding sites and increased free fraction with increased serum concentration.16
Valproate clearance is increased when more free drug is available for metabolism, and this may result in disproportionately lower steady-state serum concentrations. Smaller increases in total valproate after dosage increases may be misinterpreted as medication nonadherence.
High levels and safety
High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:
- increased nausea, vomiting, dizziness, and sedation in acutely manic patients8
- weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.12