The nature of dopamine dysfunction in schizophrenia and what this means for treatment

By Oliver D. Howes, J. Kambeitz, Euitae Kim, D. Ståhl, M. Slifstein, Anissa Abi-Dargham, Shitij Kapur. Archives of General Psychiatry, 2012

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Context Current drug treatments for schizophrenia are inadequate for many patients and, despite five decades of drug discovery, all use the same mechanism-dopamine D2 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. Data sources The MEDLINE, EMBASE and PsychINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Study selection Forty-four studies were identified that compared in vivo striatal dopaminergic function in 618 patients with schizophrenia with 606 controls using positron emission tomography or single photon emission computed tomography. Data extraction Demographic, clinical and imaging variables were extracted from each study and effect sizes determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function, and dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. Data synthesis There was a highly significant elevation (p<0.0001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen’s d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D2/3 receptor availability (Cohen’s d=0.26), but this was not evident in drug-naïve patients and was influenced by the imaging approach used. Conclusions The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic-affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release. Current drug treatments - which primarily act at D2/3 receptors - fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

Subfields: Biological Psychiatry, Cellular and Molecular Neuroscience, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/c419743a25ed07bd72a656abd0c6b28f54b31150

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In Biological Psychiatry

  1. J. Stone
  2. R. McCutcheon
  3. Oliver D. Howes

In Cellular and Molecular Neuroscience

  1. R. McCutcheon
  2. J. Stone
  3. Oliver D. Howes

In Psychiatry and Mental health

  1. R. McCutcheon
  2. J. Stone
  3. Oliver D. Howes

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