Dopamine and glutamate in schizophrenia: biology, symptoms and treatment
Tóm tắt
Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.
Từ khóa
Tài liệu tham khảo
McCutcheon RA, Schizophrenia: an overview, JAMA Psychiatry
Rossum JM, 1966, The significance of dopamine‐receptor blockade for the mechanism of action of neuroleptic drugs, Arch Int Pharmacodyn Thérapie, 160, 492
Kaar SJ, Antipsychotics: mechanisms underlying clinical response and side‐effects and novel treatment approaches based on pathophysiology, Neuropharmacology
Robinson DG, 1999, Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder, Am J Psychiatry, 156, 544, 10.1176/ajp.156.4.544
Brugger SP, Heterogeneity of striatal dopamine function in schizophrenia: meta‐analysis of variance, Biol Psychiatry
Lidow MS, 1997, Down‐regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs, J Pharmacol Exp Ther, 281, 597
Howes OD, Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi‐modal PET‐magnetic resonance brain imaging study, Neuropsychopharmacology
Braun U, 2019, Brain state stability during working memory is explained by network control theory, modulated by dopamine D1/D2 receptor function, and diminished in schizophrenia, bioRxiv, 679670
Merritt K, 2016, Nature of glutamate alterations in schizophrenia, JAMA Psychiatry, 52, 998
Kumar J, Glutathione and glutamate in schizophrenia: a 7T MRS study, Mol Psychiatry
Modinos G, 2018, Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis, Neuropsychopharmacology, 43, 262
Buzsáki G, 2012, Brain rhythms and neural syntax: implications for efficient coding of cognitive content and neuropsychiatric disease, Dialogues Clin Neurosci, 14, 345, 10.31887/DCNS.2012.14.4/gbuzsaki
Egerton A, 2017, Elevated striatal dopamine function in immigrants and their children: a risk mechanism for psychosis, Schizophr Bull, 43, 293
SongT‐A ChowdhurySR YangFet al. Super‐resolution PET imaging using convolutional neural networks. Submitted for publication.
McCutcheon R, The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta‐analysis, Mol Psychiatry