Elsevier

Biological Psychiatry

Volume 54, Issue 11, 1 December 2003, Pages 1241-1248
Biological Psychiatry

Original article
Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial

https://doi.org/10.1016/S0006-3223(03)00524-9Get rights and content

Abstract

Background

There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.

Methods

Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.

Results

In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size .7, p = .009) and general psychopathological (effect size .6, p = .030) symptoms, whereas no improvement was observed in negative symptoms.

Conclusions

These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.

Introduction

Schizophrenia severely affects quality of life and causes huge direct and indirect costs in industrialized countries as a consequence of its chronic and persistent symptomatology. When antipsychotic drugs are used to manage the symptoms, less than half of schizophrenic patients reach full remission, and 20% to 60% of the patients who receive conventional dopamine antagonist neuroleptics continue to have ongoing symptoms (Kane 1989). Clozapine has been established as the drug of choice for the treatment of those patients who are resistant to treatment with conventional neuroleptic drugs Kane et al 1988, Kane 1996. Although clozapine is considered the most efficient of known antipsychotic drugs, about half of the patients achieve only a poor or partial response with it Kane et al 1988, Tollefson et al 2001. For this reason, anticonvulsant augmentation treatments, such as valproic acid, have been widely used, although no data from controlled studies have been published to demonstrate their beneficial effectiveness.

Lamotrigine is a novel anticonvulsant drug, which has a mechanism of action based on the sodium (Na+)-channel antagonism and the inhibition of excessive glutamate release in the brain Cousin et al 1993, Grunze et al 1998, Leach et al 1991, and a large amount of evidence implicates dysfunctional glutamatergic neurotransmission in the pathophysiology of schizophrenia (for a review, see Goff and Coyle 2001). Therefore, lamotrigine is a potential treatment for schizophrenia. In two previous studies, lamotrigine in combination with clozapine was observed to be very effective in reducing symptoms measured with the Brief Psychiatric Rating Scale (BPRS) among patients with schizophrenia in open trials Dursun et al 1999, Dursun and Deakin 2001. Recently, lamotrigine was shown to be markedly superior to placebo in reducing BPRS positive symptoms induced by ketamine in healthy volunteers (Anand et al 2000). On the basis of these findings, it was decided to test whether or not lamotrigine would be more effective than placebo when combined with clozapine in treating positive symptoms of patients with schizophrenia.

Section snippets

Patients

The study protocol was approved by the ethical committee of Kuopio University Hospital. Sixty-eight patients fulfilling the inclusion criteria in the preliminary screen were selected from Niuvanniemi Hospital, Kuopio, Finland (a high-security state mental hospital that treats mentally ill criminals and treatment-resistant patients). On the basis of the results of two previous open trials Dursun et al 1999, Dursun and Deakin 2001, the sufficient sample size was estimated to be 30 patients in

Results

The 34 patients included in the study did not differ substantially from the 32 patients who refused to participate when measured by GAF (37.50 ± 8.49 vs. 40.34 ± 9.43, p > .2, t = 1.29, df = 64, Student t test). The 16 patients who received lamotrigine during the first period did not differ statistically from the 18 patients who first received placebo, according to any of their demographic and clinical characteristics, which are shown in Table 1 (p ≥ .10, Student t test). The progress of all

Discussion

These results indicate that lamotrigine combined with clozapine is more effective in the treatment of positive and general psychopathological symptoms than clozapine alone among patients with treatment-resistant schizophrenia. In the correlation analysis, there was a tendency suggesting that the beneficial effect was slightly greater among those patients who had a shorter duration of illness and who were the most resistant to clozapine treatment (having high PANSS positive symptom scores). Our

Acknowledgements

The study was supported by funding from Annual EVO Financing (Special government subsidies). No support was provided by any pharmaceutical company. We thank Mrs. Tarja Mehtonen, Ms. Aija Räsänen, and Ms. Ulla Rautamo for secretarial assistance.

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