Defining the Locus of Dopaminergic Dysfunction in Schizophrenia: A Meta-analysis and Test of the Mesolimbic Hypothesis

Abstract

BackgroundStudies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum.MethodsEMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed.ResultsTwenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges’ g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003).ConclusionIn individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Studies have consistently demonstrated raised presynaptic dopamine function in schizophrenia, with Hedges’ g=0.7 (Hedges’ g is a measure of effect size, and values of 0.2 are typically considered small, those of 0.5 medium, and those of 0.8 large). The studies using a challenge paradigm show larger effect sizes (g=1.0) compared to those quantifying dopamine synthesis capacity (g=0.5). The hyperdopaminergic state associated with schizophrenia appears greatest within the dorsal striatum.…”

“…The studies using a challenge paradigm show larger effect sizes (g=1.0) compared to those quantifying dopamine synthesis capacity (g=0.5). The hyperdopaminergic state associated with schizophrenia appears greatest within the dorsal striatum.…”

“…Finally, the PET studies discussed above have demonstrated that presynaptic dopaminergic dysfunction is greatest in the dorsal striatum, and muscarinic receptor 4 positive allosteric modulators specifically inhibit dorsal striatal dopamine release, with efficacy demonstrated in some clinical trials.…”

“…Early hypotheses had suggested that this dysfunction might be characterized by aberrant mesolimbic function. However, the use of new PET cameras has demonstrated that the greatest patient‐control differences are in the dorsal striatum. The resolution of PET is still relatively coarse, however, and this limits the precision with which inferences can be made about which specific neuron groups are affected.…”

Cortico-thalamic dysconnectivity links with aberrant striatal dopamine in schizophreniaA simultaneous18F-DOPA-PET/resting-state fMRI study

“…1-8, 21-23 Aberrant DSC, a presynaptic transmission measure assessed by 18 F-DOPA-PET, is the most consistent finding in schizophrenia, particularly in the associative-striatum (i.e., mainly caudate nucleus, contrasted to the sensorimotor-striatum; i.e., mainly putamen). 5, 24 Increased striatal-DSC is typically found in patients with significant positive symptoms 1, 4-7 and decreased striatal-DSC during remission of positive symptoms. 8, 25…”