ORGINAL ARTICLE Effect of Adjunctive Lamotrigine Treatment on the Plasma Concentrations of Clozapine, Risperidone and Olanzapine in Patients With Schizophrenia or Bipolar Disorder Edoardo Spina, MD, PhD,*† Concetta D’Arrigo, BSc,* Gaetana Migliardi, Pharm D,* Vincenza Santoro, BSc,* Maria Rosaria Muscatello, MD,‡ Umberto Mico `, MD,‡ Giuseppina D’Amico, MD,‡ and Emilio Perucca, MD, PhD§ Abstract: The effect of lamotrigine on the steady-state plasma concentrations of the atypical antipsychotics clozapine, olanzapine, and risperidone was investigated in patients with schizophrenia or bipolar disorder stabilized on chronic treatment with clozapine (200– 500 mg/day; n = 11), risperidone (3–6 mg/day; n = 10) or olanzapine (10–20 mg/day; n = 14)). Lamotrigine was titrated up to a final dosage of 200 mg/day over 8 weeks, and pharmacokinetic assess- ments were made at baseline and during treatment weeks 6 and 10, at lamotrigine dosages of 100 and 200 mg/day respectively. The plasma concentrations of clozapine, norclozapine, risperidone, and 9-hydroxy- risperidone did not change significantly during treatment with lamotrigine. The mean plasma concentrations of olanzapine were 31 6 7 ng/mL at baseline, 32 6 7 ng/mL at week 6, and 36 6 9 ng/mL at week 10, the difference between week 10 and baseline being statistically significant (P , 0.05). Adjunctive lamotrigine therapy was well tolerated in all groups. These findings indicate that lamotrigine, at the dosages recommended for use as a mood stabilizer, does not affect the plasma levels of clozapine, risperidone, and their active metabolites. The modest elevation in plasma olanzapine concentration, possibly due to inhibition of UGT1A4-mediated olanzapine glucuronidation, is unlikely to be of clinical significance. Key Words: Lamotrigine, clozapine, olanzapine, risperidone, drug interaction, pharmacokinetics (Ther Drug Monit 2006;28:599–602) INTRODUCTION Antiepileptic drugs (AEDs), particularly those with mood-stabilizing properties, are often used in combination with antipsychotics. Because many AEDs and antipsychotics share common metabolic pathways and influence the activity of various drug-metabolizing enzymes, the possibility of pharmacokinetic interactions between these drugs must be taken into account. 1,2 Lamotrigine is a second-generation AED which is wide- ly used in the treatment of bipolar disorder. 3 Recent evidence also suggests its potential role as adjunctive therapy in the management of schizophrenia. 4 Lamotrigine is predominantly metabolized by N-2-glucuronidation and, to a lesser extent, N- 5-glucuronidation. 5 These reactions are catalyzed by uridine diphosphate glucuronyltransferase (UGT) enzymes and, in particular, UGT1A4 and UGT2B7 have been identified as the major isoforms involved in lamotrigine glucuronidation. 5,6 Unlike many other AEDs, lamotrigine does not appear to inhibit or induce cytochrome P450 (CYP) enzymes, 7,8 and it is considered to be a weak inducer of UGT because it stimulates its own metabolism. 5 The ability of lamotrigine to cause a modest decrease in the plasma concentration of valproic acid 9,10 and levonorgestrel 11 could also be explained by in- duction of UGTs. Clozapine, olanzapine, and risperidone are widely used atypical antipsychotics. While clozapine is predominantly used in patients with treatment-resistant schizophrenia, risperidone and olanzapine are approved for the treatment of schizophrenia and bipolar disorder. 12,13 These agents are extensively metab- olized, primarily by oxidative processes, but also by direct glucuronidation. 14,15 Clozapine is converted by CYP1A2 and CYP3A4 to norclozapine, which has limited pharmacological activity, and by CYP3A4 to clozapine-N-oxide. Other CYP isoforms, including CYP2D6 and CYP2C19, also contribute to clozapine biotransformation. Risperidone is primarily metabolized by CYP2D6 and, to a lesser extent, CYP3A4 to 9-hydroxyrisperidone, which is approximately equipotent with the parent drug in terms of dopamine-receptor affinity. 14,15 Therefore, the total risperidone active moiety (sum of plasma concentrations of parent drug and metabolite) is regarded to contribute to the overall antipsychotic effect. 16 The major metabolic pathways of olanzapine include direct N-glucur- onidation, mediated by UGT1A4, and N-demethylation, mediated by CYP1A2. 17,18 Minor routes of olanzapine biotransformation, N-oxidation and 2-hydroxylation, are catalysed by flavin-con- taining mono-oxygenase-3 system and CYP2D6, respectively. Although lamotrigine has been used in psychiatry for many years, its potential interactions with psychotropic drugs have been little evaluated. While an in vitro investigation indicated that lamotrigine inhibits substantially olanzapine glucuronidation, 18 studies in patients and healthy subjects found From the *Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina; †IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Messina; ‡Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina; and §Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, and Institute of Neurology IRCCS C. Mondino Foundation, Pavia, Italy. Correspondence: Prof. Edoardo Spina, Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Policlinico Universitario di Messina, Via Consolare Valeria 98125 MESSINA, Italy (e-mail: espina@unime.it). Copyright Ó 2006 by Lippincott Williams & Wilkins Ther Drug Monit  Volume 28, Number 5, October 2006 599