Pharmacokinetic drug-drug interactions of mood stabilizers and risperidone in patients under Combined treatment

Schoretsanitis, Georgios; Haen, Ekkehard; Gründer, Gerhard; Stegmann, Benedikt; Schruers, Koen; Hiemke, Christoph; Lammertz, Sarah; Paulzen, Michael (2016). Pharmacokinetic drug-drug interactions of mood stabilizers and risperidone in patients under Combined treatment. Journal of Clinical Psychopharmacology, 36(6), pp. 554-561. Lippincott Williams & Wilkins 10.1097/JCP.0000000000000601

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Background: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions.
Methods: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group comedicated with valproate (VPA) (RVPA, n = 153), a group comedicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21).
Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active
moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS)
were computed.
Results: Groups did not differ with regard to the daily dosage (P = 0.46). Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM(P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups
with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the
Bonferroni correction.
Conclusions: The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AMwhen compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical
significance were found.

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