Presynaptic Dopaminergic Dysfunction in Schizophrenia: A Positron Emission Tomographic [18F]Fluorodopa Study

ArticleinArchives of General Psychiatry 61(2):134-42 · March 2004with40 Reads
DOI: 10.1001/archpsyc.61.2.134 · Source: PubMed
The dopamine overactivity hypothesis of schizophrenia remains one of the most influential theories of the pathophysiology of the illness. Radiotracer brain imaging studies are now directly testing aspects of the overactivity hypothesis. To assess presynaptic dopaminergic function in a large cohort of patients with schizophrenia by means of [18F]fluorodopa uptake and a high-sensitivity 3-dimensional positron emission tomograph. We predicted elevations in striatal [18F]fluorodopa uptake and reductions in prefrontal cortical [18F]fluorodopa uptake in patients with schizophrenia. Case-control study. Research institute investigation recruiting hospital outpatients. Sixteen male medicated hospital outpatients with a DSM-IV diagnosis of schizophrenia (mean age, 38 years) and 12 age-matched male volunteers free of psychiatric and neurologic illness. [18F]fluorodopa positron emission tomographic scanning. MAIN OUTDOME MEASURE: [18F]fluorodopa uptake constant Ki measured with statistical parametric mapping and region-of-interest analyses. Statistical parametric mapping (P<.05 corrected) and region-of-interest analyses (P<.01) showed increased [18F]fluorodopa uptake, confined primarily to the ventral striatum in patients with schizophrenia. No reductions in prefrontal cortical [18F]fluorodopa uptake Ki were seen in the statistical parametric mapping and region-of-interest analyses, although dorsal anterior cingulate [18F]fluorodopa Ki correlated with performance on the Stroop Color-Word Test in both groups. As in studies in unmedicated patients, presynaptic striatal dopamine dysfunction is present in medicated schizophrenic patients, adding further in vivo support for dopamine overactivity in the illness.
    • "First, schizophrenia has been repeatedly associated with an increase in striatal [ 18 F]DOPA and [ 11 C]DOPA uptake, which reflects an increase in presynaptic dopaminergic synthesis (Fusar- Poli and Meyer-Lindenberg 2013b). Elevated dopaminergic synthesis has been demonstrated in cohorts of patients who had been, at least in part, previously or currently medicated (Lindstrom et al. 1999; MeyerLindenberg et al. 2002; McGowan et al. 2004; Kumakura et al. 2007; Howes et al. 2009 ), and neuroleptic-na€ ıve patients (Hietala et al. 1995; Hietala et al. 1999), and has been shown to correlate with specific psychotic symptoms (McGowan et al. 2004). Persons at risk for developing schizophrenia also exhibit increased [ 18 F] DOPA uptake, which may correlate with the severity of prodromal symptoms (Howes et al. 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: Schizophrenia is a group of severe psychiatric disorders with high heritability but only low odds ratios of risk genes. Despite progress in the identification of pathophysiological processes, valid biomarkers of the disease are still lacking. Methods: This comprehensive review summarises recent efforts to identify genetic underpinnings, clinical and cognitive endophenotypes and symptom dimensions of schizophrenia and presents findings from neuroimaging studies with structural, functional and spectroscopy magnetic resonance imaging and positron emission tomography. The potential of findings to be biomarkers of schizophrenia is discussed. Results: Recent findings have not resulted in clear biomarkers for schizophrenia. However, we identified several biomarkers that are potential candidates for future research. Among them, copy number variations and links between genetic polymorphisms derived from genome-wide analysis studies, clinical or cognitive phenotypes, multimodal neuroimaging findings including positron emission tomography and magnetic resonance imaging, and the application of multivariate pattern analyses are promising. Conclusions: Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.
    Full-text · Article · Jun 2016
    • "Short-term antipsychotic treatment can alter the neurophysiological cortical response during cognitive functioning (Fusar-Poli et al., 2007). These results correlate with 'the final common pathway' hypothesis of psychosis (Howes and Kapur, 2009): both acute antipsychotic administration in HC and chronic antipsychotic medication in schizophrenia patients increase the striatal presynaptic dopamine synthesis capacity (McGowan et al., 2004). Additionally, extracellular dopaminergic levels can be elevated in the striatum (AbiDargham et al., 2000 ) and decreased in the prefrontal cortex in unmedicated schizophrenia patients (Abi-Dargham et al., 2012 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Deficits in motivational salience processing have been related to psychotic symptoms and disturbances in dopaminergic neurotransmission. We aimed at exploring changes in salience processing and brain activity during different stages of psychosis and antipsychotic medication effect. We used fMRI during the Salience Attribution Task to investigate hemodynamic differences between 19 healthy controls (HCs), 34 at-risk mental state (ARMS) individuals and 29 individuals with first-episode psychosis (FEP), including a subgroup of 17 FEP without antipsychotic medication (FEP-UM) and 12 FEP with antipsychotic medication (FEP-M). Motivational salience processing was operationalized by brain activity in response to high-probability rewarding cues (adaptive salience) and in response to low-probability rewarding cues (aberrant salience). Behaviorally, adaptive salience response was not accelerated in FEP, although they correctly distinguished between trials with low and high reward probability. In comparison to HC, ARMS exhibited a lower hemodynamic response during adaptive salience in the right inferior parietal lobule and FEP-UM in the left dorsal cingulate gyrus. The FEP-M group exhibited a lower adaptive salience response than HC in the right insula and than ARMS in the anterior cingulate gyrus. In unmedicated individuals, the severity of hallucinations and delusions correlated negatively with the insular- and anterior cingulate hemodynamic response during adaptive salience. We found no differences in aberrant salience processing associated with behavior or medication. The changes in adaptive motivational salience processing during psychosis development reveal neurofunctional abnormalities in the somatosensory and premotor cortex. Antipsychotic medication seems to modify hemodynamic responses in the anterior cingulate and insula. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · May 2015
    • "An association between aberrant dopamine neurotransmission is not only correlated with positive symptoms of the disease39,41 but has also been suggestive to be a contributing factor to cognitive deficits observed in patients.47,49 In contrast to that observed in the mesolimbic system, a decrease in dopamine transmission to the cortex may underlie deficits in working memory and executive function.50 "
    [Show abstract] [Hide abstract] ABSTRACT: Schizophrenia is a disease affecting up to 1% of the population. Current therapies are based on the efficacy of chlorpromazine, discovered over 50 years ago. These drugs block dopamine D2-like receptors and are effective at primarily treating positive symptoms in a subset of patients. Unfortunately, current therapies are far from adequate, and novel treatments require a better understanding of disease pathophysiology. Here we review the dopamine, gamma-aminobutyric acid (GABA), and glutamate hypotheses of schizophrenia and describe a pathway whereby a loss of inhibitory signaling in ventral regions of the hippocampus actually drives a dopamine hyperfunction. Moreover, we discuss novel therapeutic approaches aimed at attenuating ventral hippocampal activity in a preclinical model of schizophrenia, namely the MAM GD17 rat. Specifically, pharmacological (allosteric modulators of the α5 GABAA receptor), neurosurgical (deep brain stimulation), and cell-based (GABAergic precursor transplants) therapies are discussed. By better understanding the underlying circuit level dysfunctions in schizophrenia, novel treatments can be advanced that may provide better efficacy and a superior side effect profile to conventional antipsychotic medications.
    Full-text · Article · Jul 2014
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