New perspectives and directions in schizophrenia therapeutics: advances related to non-dopaminergic systems.

dopamine hypothesis of schizophrenia first emerged in relation to the ability of anti-dopaminergic compounds to reverse psychotic symptoms. Antipsychotics are still the gold standard for treating schizophrenia, despite their limited success in the management of negative symptoms and their side effect profile. Several non-dopaminergic hypotheses have emerged based on a variety of studies. We will focus on these non-dopamine systems and their therapeutic implications for the management of schizophrenia. Glutamate and NMDA receptor hypofunction The N-methyl-D-aspartic acid receptor (NMDAR) hypofunction hypothesis developed from the finding that drugs which block glutamate NMDARs, such as phencyclidine (PCP), induce effects almost identical to the positive and negative symptoms seen in schizophrenia. Animals given chronic doses of NMDAR antagonists developed loss of grey matter similarly reported in schizophrenia, while a relative deficit in NMDAR binding has been found in the left hippocampus of schizophrenic patients using SPECT imaging. 1 Although studies on glutamate have focused on NMDA receptors, it must be kept in mind that other glutamate receptors, both ionotropic and metabotropic, may also play a role in schizophrenia. γ-Aminobutyric acid (GABA) Patients with schizophrenia have evidence of reduced GABAergic neurotransmission in the prefrontal cortex. Drugs enhancing GABAergic function would be expected to be useful by reducing excessive cortical glutamate release. Currently, there is little or no evidence that any drugs enhancing GABA-A receptor function, such as benzodiazepines, carbamazepine or valproate are useful in schizophrenia. However, no alpha-2 subunit-selective drugs have been developed to our knowledge, and no trial of GABA-A enhancing drugs in the very early stages of the illness has yet been performed. Glycine Glycine is an amino acid that is inhibitory in the spinal cord and brain stem but also acts as a co-agonist at glutamate NMDARs. Genetic and pharmacologically-induced deficiencies in glycine binding in mice produce behavioral changes that model the negative and cognitive symptoms of schizophrenia. Several studies have tested the effects of combining glycine with certain antipsychotics or using glycine transport inhibitors with promising results. There is evidence supporting the administration of glycine and Gly-T1 transport inhibitors in order to enhance NMDAR-mediated neurotransmission for the treatment of schizophrenia. 2 D-Serine D-Serine is the main NMDAR co-agonist and it potentiates NMDAR function. Daily administration of large quantities of D-serine alone or as an adjunct to atypical antipsychotics has been reported to improve schizophrenic symptoms. D-Serine is metabolized by D-amino acid oxidase (DAO) and inactivation of DAO in mice has …