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To the Editor: A combination of clozapine and risperidone is effective in treating patients with schizophrenia who are unresponsive to other atypical antipsychotics or monotherapy with clozapine (1). Nevertheless, there are patients who respond only partially or even fail to respond to this combination. Saba et al. (2) and Dursun et al. (3) reported on patients who showed a substantial improvement of persistent positive symptoms when lamotrigine was added to clozapine therapy. There is evidence supporting the positive effects of lamotrigine based on its glutamate excess-release inhibition (4).
Because of these interesting reports, we decided to supplement the clozapine-risperidone combination of Ms. A, a 26-year-old inpatient who suffers from therapy-resistant schizophrenia with imperative auditory hallucinations, with lamotrigine. She had been taking clozapine, 550 mg/day, for 5 years and risperidone, 8 mg/day, for 4 weeks and had only responded partially. Her plasma levels of risperidone (55–70 ng/ml) and clozapine (800–1100 ng/ml) were stable. Her lamotrigine dose was titrated up to 250 mg/day in steps of 25 mg per week. After Ms. A had been taking 175 mg/day of lamotrigine for 5 days, her plasma level was 5 mg/liter, and her risperidone plasma level was 69 ng/ml. We further increased her dose of lamotrigine to 200 mg/day. Her risperidone level rose to 284 ng/ml, and in follow-up measures, it showed a value of 263 ng/ml. Her clozapine level rose to 1300 ng/ml. Ms. A did not have any intoxication symptoms. Because we did not assume any connection of increased plasma level of risperidone with lamotrigine, we heightened the dose to 225 mg/day. The next measurement of both plasma levels indicated an exorbitant increase of risperidone plasma level, up to 412 ng/ml. Ms. A complained of dizziness and tiredness. We quickly reduced the dose of risperidone to 2 mg/day and withdrew the drug 1 week later. An overdose of risperidone was unlikely since it was taken under supervision.
Metabolism of risperidone occurs mainly in the liver and is dependent mostly on cytochrome P450 isoenzyme CYP 2D6. Lamotrigine does not inhibit CYP 2D6. It is eliminated by the kidneys after glucuronidation in the liver. Until now, we have had no explanation for the increase of the risperidone plasma level during concomitant therapy with clozapine and lamotrigine. Clinicians should be aware of this effect.
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