Elevated Clozapine Plasma Level With Lamotrigine
To the Editor: Clozapine is effective in treating patients with schizophrenia who are unresponsive to, or intolerant of, classic antipsychotics (1). However, a substantial proportion of patients fail to respond to clozapine or respond only partially. Durson et al. (2) reported substantial improvement in six patients when lamotrigine, an anticonvulsant and mood stabilizer, was added to clozapine therapy in a dose of 125–250 mg/day.
Because of the promising results of this study, we prescribed lamotrigine to Mr. A, a 35-year-old outpatient. He had been taking clozapine, 400 mg/day, for 3 years and had responded partially to treatment. His plasma levels of clozapine (in six assays over 3 years) had been stable (between 300 and 500 μg/liter, measured 12 hours after a dose was taken). When lamotrigine treatment began, his clozapine plasma level was 350 μg/liter.
His lamotrigine dose was titrated up to 100 mg/day in steps of 25 mg every 2 weeks. When Mr. A had taken 100 mg/day for 2 weeks, he complained of dizziness and sedation. When we determined his plasma level of clozapine, it was found to have tripled, to 1020 μg/liter. Since Mr. A showed no clinical improvement, his lamotrigine dose was tapered over a period of 2 weeks. At the end of this period, his clozapine plasma level had returned to a therapeutic level of 450 μg/liter.
How can we explain the tripling of the patient’s clozapine plasma level during his use of lamotrigine? It is highly unlikely that the patient had taken an overdose; he was certainly not suicidal. We searched for a pharmacokinetic explanation. Drugs that are highly protein bound (e.g., warfarin) can influence clozapine plasma levels, but lamotrigine is not. The metabolism of clozapine occurs mainly in the liver and is dependent on cytochrome P-450. The P-450 isoenzymes responsible for the metabolism of clozapine have not yet been fully characterized, but CYP1A2 appears to contribute to a major extent (3). Some drugs (e.g., fluoxetine and fluvoxamine) can interfere with the metabolism of clozapine by inhibiting CYP1A2 (4). Lamotrigine, however, is believed to be free of these enzyme interactions. It is metabolized in the liver by glucuronidation and eliminated almost entirely by the kidneys (5).
Consequently, we have no explanation for the great increase in the patient’s plasma level of clozapine during concomitant use of lamotrigine. When lamotrigine is added to clozapine, clinicians should be aware of this possibility.
1. Wagstaff J, Bryson HM: Clozapine. Drugs 1990; 40:722-747Crossref, Medline, Google Scholar
2. Dursun SM, McIntosh D, Milliken H: Clozapine plus lamotrigine in treatment-resistant schizophrenia (letter). Arch Gen Psychiatry 1999; 56:950Crossref, Medline, Google Scholar
3. Bertilsson L, Carrillo JA, Dahl ML: Clozapine disposition covaries with CYP1A2 activity. Br J Clin Pharmacol 1994; 38:471-473Crossref, Medline, Google Scholar
4. Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S, Hiemke C: Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1998; 18:2-9Crossref, Medline, Google Scholar
5. Elwes RD, Binnie CD: Clinical pharmacokinetics of newer antiepileptic drugs: lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin Pharmacokinet 1996; 30:403-415Crossref, Medline, Google Scholar
