Letters to the Editor
Long-Term Lamotrigine Adjunctive to Antipsychotic Monotherapy in Schizophrenia: Further Evidence
Adding anticonvulsants to antipsychotics has been reported to improve symptoms in schizophrenia (1). Dursun and others added lamotrigine to clozapine for treatment-resistant patients and obtained positive results over 24 weeks (2,3). Saba and others obtained similar results over 12 weeks (4). We further studied the effect of long-term adjunctive lamotrigine on standard antipsychotic monotherapy (specifically, haloperidol, risperidone, or clozapine) in patients with schizophrenia.
Subjects included 10 outpatients with a DSM-IV diagnosis of schizophrenia (8 men and 2 women aged 22 to 49 years; mean age, 30.7 years) enrolled in the following studies: RIS-INT-35 (n = 7), a double-blind study of risperidone vs haloperidol in new-onset schizophrenia; RIS-INT-57 and RIS-INT-63, (RIS-CONSTA studies, n = 1 each); and InterSePT study (n = 1) of clozapine vs olanzapine in suicidal patients with schizophrenia (5). Lamotrigine was used as open-label adjunctive therapy. The mean daily dosage of lamotrigine was 232.5 mg (range 25 to 400 mg/daily) over a mean period of 132 weeks (range 30 to 220 weeks).
Patients were treated for up to 220 weeks with no relapses. The medication was well tolerated, with no major adverse events. We measured changes in Positive and Negative Symptoms Scale (PANSS) scores and Clinical Global Impression (CGI) scores from initiation of lamotrigine to most recent observation. No patient worsened significantly. Six out of 10 patients showed an average improvement of 1.5 points on the CGI. The mean (SD) change in CGI for the entire group was 4.1 (0.9) to 3.2 (0.8). Two of 10 patients had a marked decrease in their total PANSS scores (–39 and –49 points). The mean (SD) change in total PANSS score for the entire group was 77.3 (35.1) to 64 (25.5).
A model of psychosis based on N-methyl-D-aspartate (NMDA) antagonists (specifically, phencyclidine or ketamine) proposes that NMDA- receptor hypofunction contributes to the pathophysiology of schizophrenia (6). Anand and others reported that lamotrigine attenuates the neuropsychiatric effects of ketamine in healthy volunteers (7). Olney and others propose that lamotrigine may compensate for the functional hypo-NMDA state by suppressing excessive glutamate release and the spread of abnormal neural activity occurring in schizophrenia (8). Abnormal glutamatergic neurotransmission in the prefrontal cortex may represent a mechanism by which stress exacerbates symptoms in this vulnerable population (9).
Our data are consistent with the report of Dursun and others (2). We conclude that the addition of lamotrigine to low-dose risperidone, haloperidol, or clozapine produces overall benefit in patients with schizophrenia, including first-episode patients. Controlled clinical trials are warranted to evaluate efficacy and to clarify which patients benefit most from adjunctive lamotrigine.
1. Wassef AA, Dott SG, Harris A, Brown A, O’Boyle M, Meyer WJ III, and others. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 2000;20:357–61.
2. Dursun SM, McIntosh D, Milliken H. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch Gen Psychiatry 1999;56:950.
3. Dursun SM, Deakin JF. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study.
J Psychopharmacol 2001;15:297–301.
4. Saba G, Dumortier G, Kalalou K, Benadhira R, Degrassat K, Glikman J, and others. Lamotrigine– clozapine combination in refractory schizophrenia: three cases. J Neuropsychiatry Clin Neurosci 2002;14:86.
5. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, and others. Clozapine treatment for suicidality in schizophrenia International Suicide Prevention Trial (InterSePT). Arch general Psychiatry 2003;60: 82–91.
6. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001;158:1367–77.
7. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, and others. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000;57:270–6.
8. Olney JW, Newcomer JW, Farber NB. Is NMDA receptor hypofunction in schizophrenia associated with a primary hyperglutamatergic state? Arch Gen Psychiatry 2002;59:466–8.
9. Moghaddam B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry 2002;51:775–87.
Theodore T Kolivakis, MD, CM, FRCPC,
Linda Beauclair, MD, FRCPC,
Howard C Margolese, MD, CM, FRCPC,
Guy Chouinard, MD, MSc, FRCPC,