title: Interactions between valproic acid and quetiapine/olanzapine in the treatment of bipolar disorder and the role of therapeutic drug monitoring.
abstract: OBJECTIVE
  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 drug-drug interaction, bipolar disorder, therapeutic drug monitoring.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vella
authors.forename: Janet
authors.initials: J
authors.lastname: Mifsud
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D003987:Dibenzothiazepines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D006801:Humans; D000077152:Olanzapine; D000069348:Quetiapine Fumarate; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D014635:Valproic Acid; D000077152:Olanzapine
keywords: drug-drug interactions; olanzapine; quetiapine; therapeutic drug monitoring; valproic acid