Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework

Background There is a lack of consensus on the optimal serum valproic acid (VPA) concentration for maintenance therapy in bipolar disorder (BD). We aimed to investigate the association between serum VPA levels and risk of mood episode recurrence.Methods We enrolled patients with BD from multiple medical institutions in Taiwan between January 1, 2001 and December 31, 2019. Patients were divided into three groups according to their serum VPA concentrations (< 50 mu g/ ml, 50-74 mu g/ml, and 75-104 mu g/ml). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) compared times to mood episode recurrence using the < 50 mu g/ml group as reference. A systematic review found relevant articles published before February 2022 (PROSPERO: CRD42022309661), and corresponding results were compared.Findings This cohort included 896 patients for an intention-to-treat analysis. Compared with the < 50 mu g/ml group, a non-significantly lower risk of mood episode recurrence was found in the 50-74 mu g/ml (aHR, 95% CI: 0.86, 0.71 -1.05) and 75-104 mu g/ml (0.91, 0.71-1.18) groups. A per-protocol analysis of 481 patients found a significant risk reduction in the 50-74 mu g/ml group (0.76, 0.60-0.97), with inconclusive results in the >= 75 mu g/ml group (1.03, 0.73-1.46). A meta-analysis including two studies (254 patients) and our cohort found a similar significantly lower risk of mood episode recurrence in the 50-74 mu g/ml group (HR, 95% CI: 0.83, 0.69-0.99), while risk reduction in the 75-99 mu g/ml group (0.62, 0.26-1.48) did not differ significantly from that in the < 50 mu g/ml group or the 50-74 mu g/ml group.Interpretation The combined results of this cohort and previous studies suggest that VPA between 50-74 mu g/ml may be a more effective concentration to prevent acute mood episodes during maintenance therapy in patients with BD compared with VPA < 50 mu g/ml.Funding Ministry of Science and Technology, Taiwan, and Chang Gung Medical Research Project.Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

This study investigates the association between serum valproic acid levels and risk of mood episode recurrence in bipolar disorder patients. The findings suggest that maintaining a serum valproic acid concentration between 50-74 μg/ml may be more effective in preventing acute mood episodes in patients with bipolar disorder compared to a concentration below 50 μg/ml.