title: Neuroprogression in schizophrenia: Pathways underpinning clinical staging and therapeutic corollaries.
abstract: OBJECTIVE
  Whilst dopaminergic dysfunction remains a necessary component involved in the pathogenesis of schizophrenia, our current pharmacological armoury of dopamine antagonists does little to control the negative symptoms of schizophrenia. This suggests other pathological processes must be implicated. This paper aims to elaborate on such theories.
  
  
  METHODS
  Data for this review were sourced from the electronic database PUBMED, and was not limited by language or date of publication.
  
  
  RESULTS
  It has been suggested that multiple 'hits' may be required to unveil the clinical syndrome in susceptible individuals. Such hits potentially first occur in utero, leading to neuronal disruption, epigenetic changes and the establishment of an abnormal inflammatory response. The development of schizophrenia may therefore potentially be viewed as a neuroprogressive response to these early stressors, driven on by changes in tryptophan catabolite (TRYCAT) metabolism, reactive oxygen species handling and N-methyl d-aspartate (NMDA) circuitry. Given the potential for such progression over time, it is prudent to explore the new treatment strategies which may be implemented before such changes become established.
  
  
  CONCLUSIONS
  Outside of the dopaminergic model, the potential pathogenesis of schizophrenia has yet to be fully elucidated, but common themes include neuropil shrinkage, the development of abnormal neuronal circuitry, and a chronic inflammatory state which further disrupts neuronal function. Whilst some early non-dopaminergic treatments show promise, none have yet to be fully studied in appropriately structured randomized controlled trials and they remain little more than potential attractive targets.
authors.affiliation: IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, Geelong, Australia justinbdavis19@gmail.com.
authors.forename: Justin
authors.initials: J
authors.lastname: Davis
authors.affiliation: IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, Geelong, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Moylan
authors.affiliation: Division of Pharmacology, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North West University, Potchefstroom, South Africa.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
authors.affiliation: IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, Geelong, Australia Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
authors.affiliation: IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, Geelong, Australia Orygen Youth Health Research Centre, Parkville, Australia Centre of Youth Mental Health, University of Melbourne, Parkville, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia University of Melbourne, Department of Psychiatry, Royal Melbourne Hospital, Parkville, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Epigenetics; NMDA; TRYCATs; inflammation; mitochondrial dysfunction; neuroprogression; oxidative stress; schizophrenia