The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway

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.

Overshadowing depends on cue and reinforcement sensitivity but not schizotypy

“…Deficiencies in LI and/or KB are said to reflect 'hyperassociability', whereby individuals form associations about cues which erroneously appear as salient, consistent with more recent theories proposing that psychosis can be understood in terms of aberrant salience processing [16][17][18].…”

A Review of the Functional and Anatomical Default Mode Network in Schizophrenia

“…Furthermore, recent imaging genetic investigations have shown that gene polymorphisms of catechol-O-methy1 transferase [60] and DA receptor [61], which are associated with cortical DA levels, regulate the activity and connectivity strength of the MPFC and PCC/PCUN. All this strong evidence suggests a potential modulatory role of the DMN in antipsychotic medications, as all antipsychotic drugs bind to the DA receptor [62].…”

Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia

“…D2 receptor activity appears to play a key role in the metabolic rate of the striatum [78,79] and dopamine is important in the regulation of the striatum by the prefrontal cortex [80]. A significant number of gene variants associated with schizophrenia are implicated directly or indirectly in the dopaminergic system [81] and it is a possibility that the rare deletions included in the present study are disproportionately affecting this pathway. The striatum is also a key region in the interaction of the dopaminergic and glutamatergic systems [82] with a recent genetic pathway analysis strongly implicating the glutamatergic system in schizophrenia [83].…”