title: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
abstract: BACKGROUND
  Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.
  
  
  OBJECTIVE
  To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.
  
  
  METHODS
  The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.
  
  
  METHODS
  A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.
  
  
  METHODS
  Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.
  
  
  RESULTS
  There was a highly significant elevation (P.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.
  
  
  CONCLUSIONS
  The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, Camberwell, UK. oliver.howes@kcl.ac.uk
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.forename: Joseph
authors.initials: J
authors.lastname: Kambeitz
authors.forename: Euitae
authors.initials: E
authors.lastname: Kim
authors.forename: Daniel
authors.initials: D
authors.lastname: Stahl
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D009480:Neuropharmacology / Q000379:methods; D018377:Neurotransmitter Agents / Q000096:biosynthesis / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018377:Neurotransmitter Agents; D011954:Receptors, Dopamine; D004298:Dopamine