The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway
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Open Access
- 30 March 2009
- journal article
- review article
- Published by Oxford University Press (OUP) in Schizophrenia Bulletin
- Vol. 35 (3), 549-562
- https://doi.org/10.1093/schbul/sbp006
Abstract
The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.Keywords
This publication has 143 references indexed in Scilit:
- Genetic associations with schizophrenia: Meta-analyses of 12 candidate genesSchizophrenia Research, 2008
- Large recurrent microdeletions associated with schizophreniaNature, 2008
- Prediction of Psychosis in Youth at High Clinical RiskArchives of General Psychiatry, 2008
- Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trialNature Medicine, 2007
- Neurocognitive deficits in the (putative) prodrome and first episode of psychosisSchizophrenia Research, 2007
- Cognitive Functioning in the Schizophrenia ProdromeSchizophrenia Bulletin, 2007
- Biological, Life Course, and Cross-Cultural Studies All point Toward the Value of Dimensional and Developmental Ratings in the Classification of PsychosisSchizophrenia Bulletin, 2007
- Generalized and Specific Cognitive Performance in Clinical High-Risk Cohorts: A Review Highlighting Potential Vulnerability Markers for PsychosisSchizophrenia Bulletin, 2005
- Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophreniaNature Neuroscience, 2002
- A Neural Substrate of Prediction and RewardScience, 1997