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Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies

  • Joseph Kambeitz (a1), Anissa Abi-Dargham (a2), Shitij Kapur (a1) and Oliver D. Howes (a3)

The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential.


To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia.


Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions.


The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d =–0.32 (95% CI –0.68 to 0.03) for the thalamus, d =–0.23 (95% CI –0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI –0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus.


There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.

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      Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies
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Corresponding author
Oliver D. Howes, BM, BCh, MA, MRCPsych, PhD, DM, Department of Psychosis Studies, Institute of Psychiatry, King's College London, PO Box 67, Camberwell, London SE5 8AF, UK. Email:
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This study was funded by a Medical Research Council (UK) grant to O.D.H. (grant number: MC-A656-5QD30) and the National Institute of Health Research Biomedical Research Council.

Declaration of interest

O.D.H has consulted for and/or spoken at events organised by AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Roche and Sunovion. A.A.-D. has consulted or given lectures for Sunovion, Shire, and Bristol-Myers Squibb/Otsuka. S.K. has received grant support from AstraZeneca and GlaxoSmithKline and has served as consultant and/or speaker for AstraZeneca, Bioline, Bristol-Myers Squibb/Otsuka, Eli Lilly, Janssen (Johnson & Johnson), Lundbeck, Neuro-Search, Pfizer, Roche, Servier, and Solvay/Wyeth.

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Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies

  • Joseph Kambeitz (a1), Anissa Abi-Dargham (a2), Shitij Kapur (a1) and Oliver D. Howes (a3)
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Arn't we scraping the barrel now?

Prasanna N. de Silva, Consultant Old Age Psychiatrist
13 June 2014

Kambeitz and colleagues (1) have found no meaningful evidence of frontal hypodoperminergia in their well designed meta-analysis. This is embarrassing, as the current version of the Dopamine Hypothesis rests on reduced dopamine distribution to the Frontal lobe, with excess dopamine input to sub cortical (striatal and mesolimbic) areas. Certainly there is no evidence for the original Dopamine hypothesis of excess Dopamine production in the brain, which was assumed from the effectiveness of dopamine blockers in treating so called positive symptoms.

Should we now break out of this mental construct, and look at other possibilities of reduced frontal metabolism? This could be either due to neuronal membrane problems like brain GLUT (glucose transporter) deficits (2) or intra neuronal problems in the metabolic pathway (3) either within or out with mitochondria. In both these situations, pathology would be both neurodevelopmental and neurodegenerative in nature, thereby releasingus out of that dichotomy as well.

Perhaps the variation of metabolism seen within the cortex (suggestedby reduced perfusion and glucose uptake) might be the result of each humanusing different parts of the brain (or different circuits)due to their preferred activity or talents. Therefore unlike dementia where the advice is 'use it or lose it', pathophysiology in schizophrenia could be based onthe idea of 'use it and lose it'

The search for alternative constructs to explain schizophrenia has been given extra impetus by the accumulating evidence of dose related cortical thinning over time in patients using dopamine blockers (4), including the atypical drugs currently in vogue.

An alternative paradigm might just release us to look for non dopaminergic treatments. There is the other issue of what exactly we tell patients and carers about aetiology and pathogenesis following this negative result coupled with the finding of progressive cortical thinning caused by our drugs.

References1.Kambeitz, J., Abi-Dargham, A., Kapur, S., and Howes, O. Alterations in cortical and extra striatal sub cortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. TheBritish Journal of Psychiatry 2014 Vol 204 pp 420-4292.McDermott E., de Silva P.N. Impaired neuronal glucose uptake in pathogenesis of schizophrenia - can GLUT 1 and GLUT 3 deficits explain imaging, post mortem and pharmacological findings? Medical Hypothesis, 2005 Vol 65, pp 1076 -1081, 20053.Girgis, R.R., Javich, J.A., Lieberman, J.A. (2008) Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effectsand insulin signalling pathway. Molecular Psychiatry 2008 Vol 8, pp 1-124.Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia. Arch Gen Psychiatry 2011 Feb;68(2):128-37

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