Growing evidence for glutamate abnormalities in schizophrenia support the development of novel antipsychotic agents targeting this system. Early studies investigating modulation of the glutamate system using glycine, D-serine and sarcosine in patients with schizophrenia have demonstrated significant effects, particularly on negative symptoms, conventionally thought to be refractory to antipsychotic drug treatment. Drugs targeting the glutamate system also have a completely different side-effect profile to dopamine D2 antagonists, with no propensity to extrapyramidal side effects, prolactinaemia or weight gain. It has been hypothesized that glutamatergic drugs may be of benefit to the 20–30% of individuals with schizophrenia who fail to show any response to dopaminergic agents, and may be particularly useful in the early stages of the illness, where they may be disease-modifying. A number of glutamatergic compounds have been reported as having promising results in phase II drug trials. If these reach the clinic, they will represent the first truly novel approach to pharmacotherapy in schizophrenia for more than 50 years.
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