the metabotrophic receptors [200,201]. However, it would appear that other subtypes of the NMDA receptor increase in response to effective therapies. Such findings underpin the application of drugs that activate the NMDA receptors as possible novel antipsychotic medications. Thus, glycine and d-serine, as NMDA receptor agonists, have been studied for their potential antipsychotic effects. High doses of glycine (30-60 g/day) have been shown to improve the negative symptoms in schizophrenia . d-Serine, a full agonist at the NMDA-receptor glycine site, was also reported to improve the negative symptoms, psychosis and cognitive functioning of patients with schizophrenia , while d-cycloserine, a partial agonist of the glycine site, was shown to improve the negative symptoms when added to conventional neuroleptic drugs, without improving cognitive function . These preliminary clinical findings support the possible value of drugs that enhance glycine-receptor function, at least in the treatment of the negative symptoms of schizophrenia.
Several compounds that act as positive modulators of the AMPA receptors have also been studied. Of these, CX516 (AMPALEX, Novartis, Basel, Switzerland) was shown to improve the attention, memory and distractibility of patients, and also produced a significant improvement in cognitive function [211,212]. Thus, it would appear that agonists of the glycine site on the NMDA receptor, and modulators of the AMPA receptors, may prove to be novel antipsychotic medications in the future.
Sigma receptors and antipsychotic action
Since the discovery that the psychotomimetic benzomorphans act on sigma receptors in the brain, while some antipsychotic drugs such as haloperidol and remoxipride act as sigma-receptor antagonists, attention has been directed towards the development of sigma-receptor antagonists as potential antipsychotic agents . Several sigma antagonists have been clinically tested over the past 17 years. However, most trials to date involve few patients; few studies have been replicated and many of the first sigma agents to be tested were also antagonists of 5HT2 receptors (e.g. rimcazole, tiosperone). Of the more specific sigma antagonists, panamesine (EMD 57445) has been the subject of three trials involving a small number of patients. Panamesine was found to exert acute antipsychotic effect, at least in some patients . Eliprodil (SL 820715) is also a sigma ligand but, in addition, has NMDA-antagonistic properties that could limit its efficacy. In an open trial, eliprodil was shown to improve the negative symptoms in a small number of patients . A potent selective sigma antagonist, SR-31742, is also currently undergoing clinical trials in schizophrenia, the results of which may provide conclusive evidence regarding the antipsychotic potential of such drugs. Thus it appears that there is some evidence that sigma antagonists may have antipsychotic potential, but more detailed clinical studies are required to substantiate this.
GABAaergic receptors and antipsychotic action
Experimental studies have demonstrated that the y-aminobutyric acid (GABA)-A receptors have an inhibitory action on the dopaminergic system while the GABA-B receptors have an indirect stimulatory action on these receptors. Thus, it is anticipated that GABA-A-receptor agonists might be of some value in the treatment of schizophrenia. Of the drugs available, the benzodiazepines