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The potential role of lamotrigine in schizophrenia

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Abstract

Rationale

Atypical antipsychotic drugs are the drugs of choice for the treatment of schizophrenia. However, despite advances, no treatments have been established for patients who fail to improve with the most effective of these, clozapine. The inhibition of dopamine transmission through blockade of dopamine D2 receptors is considered to be essential for antipsychotic efficacy, but it is postulated that modulation of glutamate transmission may be equally important. In support of this, symptoms similar to schizophrenia can be induced in healthy volunteers using N-methyl-d-aspartate (NMDA) antagonist drugs that are also known to enhance glutamate transmission. Furthermore, lamotrigine, which can modulate glutamate release, may add to or synergise with atypical antipsychotic drugs, some of which may themselves modulate glutamate transmission.

Objectives

We examine the evidence for the efficacy of lamotrigine. We consider how this fits with a glutamate neuron dysregulation hypothesis of the disorder. We discuss mechanisms by which lamotrigine might influence neuronal activity and glutamate transmission, and possible ways in which the drug might interact with antipsychotic medications.

Results

Data from four clinical studies support the efficacy of adjunctive lamotrigine in the treatment of schizophrenia. In addition, and consistent with a glutamate neuron dysregulation hypothesis of schizophrenia, lamotrigine can prevent the psychotic symptoms or behavioural disruption induced by NMDA receptor antagonists in healthy volunteers or rodents.

Conclusions

The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs.

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Acknowledgements

The authors thank Mrs. Barbara Wilson, Drs. Dan Javitt, Gary Evoniuk, Dr. Jo Neill and Prof. Mark Geyer for helpful discussion. We would also like to thank the reviewers for their many valuable comments, suggestions, and encouragement.

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Authors and Affiliations

  1. Department of Neuropharmacology, Psychiatry CEDD, GlaxoSmithKline SpA, Via Fleming 4, 37135, Verona, Italy

    Charles H. Large

  2. MDC Clinical Psychiatry North America, GlaxoSmithKline Inc., 5 Moore Drive, Research Triangle Park, NC, USA

    Elizabeth L. Webster

  3. Schizophrenia Program, Massachusetts General Hospital, 25 Staniford Street, Boston, MA, USA

    Donald C. Goff

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  1. Charles H. Large
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Large, C.H., Webster, E.L. & Goff, D.C. The potential role of lamotrigine in schizophrenia. Psychopharmacology 181, 415–436 (2005). https://doi.org/10.1007/s00213-005-0020-9

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