Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment.
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 AM when 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.
From the *Departmentof Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University and JARA-Translational Brain Medicine, Aachen, Germany; †University Hospital of Psychiatry, Bern, Switzerland; ‡Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany; §Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; ∥Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Germany.
Georgios
G
Schoretsanitis
Ekkehard
E
Haen
Gerhard
G
Gründer
Benedikt
B
Stegmann
Koen R J
KR
Schruers
Christoph
C
Hiemke
Sarah E
SE
Lammertz
Michael
M
Paulzen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000097:blood*; D001714:Bipolar Disorder / Q000188:drug therapy*; D002220:Carbamazepine / Q000494:pharmacology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000097:blood*; D018967:Risperidone / Q000097:blood*; D014227:Triazines / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*; D055815:Young Adult
D000927:Anticonvulsants; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D018967:Risperidone; D000068882:Paliperidone Palmitate; D000077213:Lamotrigine