Glutamatergic hypothesis of schizophrenia

Schizophrenia is a devastating psychiatric disorder whose pathophysiology has not been fully clarified yet. Although dopamine dysfunction in schizophrenia is unequivocal, there are many evidences suggesting the involvement of the glutamatergic system. This paper briefly describes some basic knowledge regarding the functioning of the glutamatergic receptors with emphasis on the N-methyl-D-aspartate (NMDA) receptors. Presents evidence for glutamatergic dysfunction in schizophrenia, more specifically NMDA receptor hypofunction. Finaly the paper discusses the interaction between the dopaminergic and the glutamatergic systems; in special how hyperdopaminergic state found in schizophrenia can be associated to glutamatergic dysfunctions.A esquizofrenia é um transtorno psiquiátrico devastador cuja fisiopatologia ainda está para ser esclarecida. Apesar de uma disfunção dopaminérgica estar bem estabelecida na esquizofrenia, há uma série de evidências sugerindo o envolvimento do sistema glutamatérgico na fisiopatologia do transtorno. Este artigo faz uma breve revisão de alguns aspectos básicos do funcionamento dos receptores glutamatérgicos com ênfase nos receptores N-metil-D-aspartato (NMDA). Apresenta evidências científicas sugerindo uma disfunção do sistema glutamatérgico na esquizofrenia (hipofunção de receptores NMDA). E discute as interações entre os sistemas dopaminérgico e glutamatérgico; mais especificamente como os estados hiperdopaminérgicos encontrados na esquizofrenia podem estar associados a uma alteração glutamatérgica.Universidade Federal de São Paulo (UNIFESP) Departamento de PsiquiatriaKing's College London Institute of Psychiatry Section of Neurochemical ImagingUNIFESP, Depto. de PsiquiatriaSciEL

Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs—An Original Patient Data Meta-analysis of the SPECT and PET In Vivo Receptor Imaging Literature

Subject numbers in neuroreceptor imaging studies of antipsychotic treatment in schizophrenia are generally insufficient to directly test the relationship of regional D2/D3 and 5HT2A receptor binding to clinical efficacy. We selected positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of antipsychotic dose vs occupancy at both temporal cortex and striatal D2/D3 receptors. We selected corresponding SPECT and PET studies of 5HT2A receptor occupancy. We also selected randomized double-blind clinical trials of antipsychotics, where patients were treated with randomly assigned fixed doses. For each antipsychotic drug, we compared the optimum effective antipsychotic dose with the dose inducing maximal occupancy of D2/D3 receptors in striatum and in temporal cortex as well as at 5HT2A receptors. Both first- and second-generation antipsychotic (FGA, SGA) drugs produced high temporal cortex D2/D3 occupancy. Only FGA produced high striatal D2/D3 receptor occupancy. The clinically effective dose showed correlation with doses inducing maximal dopamine D2/D3 receptor occupancy both in striatum and in temporal cortex, the strongest correlation being with temporal cortex binding. Extrapyramidal side effects (EPSE) were primarily related to striatal D2/D3 receptor occupancy. There was no correlation between 5HT2A occupancy and clinically effective dose. We conclude that cortical dopamine D2/D3 receptor occupancy is involved in antipsychotic efficacy, with striatal D2/D3 occupancy having a likely therapeutic role while also inducing EPSE. We found no evidence for 5HT2A blockade involvement in antipsychotic action, although we cannot exclude this possibility