Clozapine Plus Lamotrigine in Treatment-Resistant Schizophrenia

C lozapine is the only antipsychotic agent with proven efficacy in treatment-resistant schizophrenia; however, a substantial minority of patients fail to respond or have only a partial response to clozapine, leading clinicians to search for potential augmentation strategies to improve outcomes. To date, these augmentation strategies with clozapine have generally been disappointing. Glutamate is an excitatory neurotransmitter, and clozapine acts as a glutamate antagonist. Lamotrigine, an anticonvulsant and mood stabilizer, inhibits excessive release of glutamate. Both drugs block the psychotomimetic effects of phencyclidine (PCP). These schizophrenia-like symptoms are attributed to PCP’s activity at the NMDA (glutamate) receptor. The biochemical significance of these glutamate interactions in schizophrenia remains unclear and is hotly debated. There is evidence to suggest that there is abnormal glutamatergic binding in the areas of the brain associated with psychotic symptoms in patients with schizophrenia. We are reporting on a small, open-label, nonrandomized case series of 6 outpatients who had a partial response to clozapine. All patients were taking the maximum tolerated dose of clozapine, with lamotrigine added as an augmentation strategy. Clozapine dosages were stable at the time lamotrigine therapy was initiated and remained the same throughout the 24-week period monitored by the Brief Psychiatric Rating Scale. No patient dropped out of the study. All patients had therapeutic plasma clozapine levels and had been taking clozapine for a minimum of 16 months. Lamotrigine therapy was initiated at 12.5 mg/d and titrated by patient response. When baseline Brief Psychiatric Rating Scale scores were compared with scores in each subsequent week using a pairwise approach for the sample, all were found to be significantly different (P#.05) by Wilcoxon signed rank test (Table). Reported side effects included headache, sedation, dizziness, and mild hand tremor. No dermatological side effects were observed, and none of the side effects were considered disturbing by the patients. Despite the significant limitations of a small sample size and open-label, nonrandomized design, the preliminary data suggest that clozapine plus lamotrigine may be a useful augmentation for treatment-resistant schizophrenia. Clozapine is metabolized primarily through the liver CYP450 system (isoenzyme 1A2), while lamotrigine is metabolized in the liver by glucuronidation. Therefore, any synergism between the 2 is very likely pharmacodynamic (perhaps involving glutamate and/or nitric oxide) rather than the result of a pharmacokinetic interaction. We believe this finding warrants further study.