Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross‐sectional study

Abstract

IntroductionThe debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM.MethodsThe present cross‐sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non‐remission on Young's mania rating scale (YMRS).ResultsThe intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non‐remission, but the comparison between the two ROC analyses was not statistically significant.ConclusionFree valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

Letter to the editor—Reflections on “Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross‐sectional study”

“…

The recent comparative analysis between total and free valproate levels for bipolar disorder concluded that there is no significant difference in their clinical effectiveness (Krishna et al, 2024). However, the implications of these findings on patients with liver dysfunction deserve further consideration, particularly because drug protein binding changes could alter drug dynamics.Research by Wei et al (2011) showed no significant liver function test differences between psychiatric patients with Hepatitis B on valproic acid and those not on the medication, suggesting a stable safety profile for this patient group (Wei et al, 2011).

…”

“…The recent comparative analysis between total and free valproate levels for bipolar disorder concluded that there is no significant difference in their clinical effectiveness (Krishna et al, 2024). However, the implications of these findings on patients with liver dysfunction deserve further consideration, particularly because drug protein binding changes could alter drug dynamics.…”