Interactions between valproic acid and quetiapine/olanzapine in the treatment of bipolar disorder and the role of therapeutic drug monitoring

Abstract

Objectives The anticonvulsant valproic acid and the atypical antipsychotics olanzapine and quetiapine provide synergistic mood-stabilising, antidepressant and antipsychotic activities in the treatment of bipolar and schizoaffective disorders. Existing literature shows that pharmacokinetic and pharmacodynamics drug-drug interactions (DDIs) possibly occur with the use of such a combination. Clinical reports of a possible interaction between the drugs leading to an increased risk of adverse drug reactions have also emerged. The main objective of this paper is to review the incidence of DDIs between the anticonvulsant and the antipsychotics, to postulate the possible mechanisms of the interaction and to establish whether certain target populations are at an increased susceptibility to such interactions. The usefulness of therapeutic drug monitoring (TDM) of the antipsychotics to monitor for an interaction was also assessed. A systematic database search was carried out using the search engine provided by PubMed using the following key words: olanzapine, quetiapine, valproic acid, pharmacokinetic drugdrug interaction, bipolar disorder, therapeutic drug monitoring. Key findings Evidence of a possible clinically relevant DDI between valproic acid and both antipsychotics has been uncovered. A possible mechanism for the interactions has been postulated, and the importance of TDM has been discussed. Summary Further research is required to determine whether DDIs occur with the concurrent use of valproic acid and olanzapine or quetiapine, and to investigate the potential of TDM as a clinical tool in improving pharmacotherapy and preventing toxicity.

Relationship Between Daily Dose, Serum Concentration, and Clinical Response to Quetiapine in Children and Adolescents with Psychotic and Mood Disorders

“…Although valproic acid is not metabolized via CYP3A4 and CYP2D6 but via glucuronosyltransferase [9], it has been shown that co-medication with valproic acid was associated with a 77 % increase in quetiapine plasma concentration [19]. This interaction has been shown to be clinically relevant [20]. Because in our study only 6 of 180 patients were co-prescribed valproic acid, we were not able to demonstrate this pharmacokinetic drug interaction.…”

Severe recurrent hypothermia in an elderly patient with refractory mania associated with atypical antipsychotic, valproic acid and oxcarbazepine therapy

“…There are reports in the literature noting increase in rare side effects following VPA coadministration with olanzapine and quetiapine, respectively. 20 VPA was noted to increase plasma concentration of quetiapine by 77% when coadministered. 21 An analysis on the interaction between VPA and olanzapine/quetiapine noted that VPA decreases plasma concentration of olanzapine and increases plasma concentration of quetiapine.…”

Evaluation of potential drug-drug interactions in psychiatric patients: a pilot study

“…An early review on hematological side effects of psychotropic drugs mentions valproic acid as causing anemia, neutropenia, pure red cell aplasia and thrombocytopenia, and olanzapine as inducing leukocytosis and thrombocytopenia (19). Furthermore, recent evidence associates olanzapine with leukopenia, even recommending that the guidelines for using and monitoring olanzapine be reconsidered (20)(21)(22).…”

“…Use of psychotropic drugs with minimal liver metabolism and monitoring the levels of aminotransferases is considered appropriate in such occasions (28,29). Other ADRs that olanzapine and valproate share are weight gain, somnolence, tremor, dry mouth, and speech disorders (20).…”