Heterogeneity of Striatal Dopamine Function in Schizophrenia: Meta-analysis of Variance

Brugger, Stefan; Angelescu, Ilinca; Abi‐Dargham, Anissa; Mizrahi, Romina; Shahrezaei, Vahid; Howes, Oliver

doi:10.1016/j.biopsych.2019.07.008

Cited by 81 publications

(63 citation statements)

References 71 publications

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“…A summary of all the direct and indirect evidences of striatal DA alterations in SCZ was recently published ( McCutcheon et al., 2020 ). All data confirm the presence of presynaptic DA sensitization and elevated DA synthesis and release capacity ( Brugger et al., 2020 ; Weidenauer et al., 2020 ). Higher striatal DA synthesis and higher DA release correlated with worsening of psychotic symptoms in SCZ patients and were also supported by neuromelanin observation ( Weinstein et al., 2017 ).…”

Section: Section 2: Dr Alterations In Schizophreniasupporting

confidence: 75%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

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Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.

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Section: Section 2: Dr Alterations In Schizophreniasupporting

confidence: 75%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

View full text Add to dashboard Cite

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“…DAT is involved in reuptake of dopamine from the synaptic cleft, and is often interpreted in PET studies as a measure of the density of dopamine neurons. Studies examining DAT density in the striatum have found no consistent differences between patients and controls, although, as with D2 receptors, variability is increased in schizophrenia, suggesting that differences may exist within a subgroup. A more recent study did find significantly raised striatal DAT levels in patients, but this was observed in those with a chronic illness with long‐term antipsychotic exposure.…”

Section: Dopaminementioning

confidence: 99%

“…Finally, it has recently been shown that the variability of striatal D2 receptor levels is greater in patients than controls, suggesting that differences in D2 receptor density may exist, but only within a subgroup of patients, although whether this reflects a primary pathology or an effect of prior antipsychotic treatment in some patients remains unclear.…”

Section: Dopaminementioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

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“…This suggests that the mechanism underlying positive symptoms could be central to the relationship between DUP and outcomes. Striatal dopaminergic dysfunction is thought to underlie the development of psychosis 71,72 , and it has been hypothesized that psychosis feeds back on the regulation of dopamine neurons to cause further dysregulation 73,74 . Thus, a longer DUP could lead to continuing progression of dopaminergic dysfunction that makes the system less responsive to D2 antagonism when antipsychotic treatment is started 75 .…”

Section: Findings and Comparison With Previous Studiesmentioning

confidence: 99%

The clinical significance of duration of untreated psychosis: an umbrella review and random‐effects meta‐analysis

et al. 2021

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The idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health services worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta‐analyses and performed a random‐effects meta‐analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta‐analyses of studies including patients with schizophrenia spectrum disorders, first‐episode psychosis, or affective and non‐affective psychosis. Thirteen meta‐analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta‐analyses. We therefore conducted a new random‐effects meta‐analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non‐significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=–0.07, p=3.6×10–5) and higher chance of previous self‐harm (odds ratio, OR=1.89, p=1.1×10–5). At follow‐up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=–0.16, p=4.5×10–8), more severe negative symptoms (beta=–0.11, p=3.5×10–10) and lower chance of remission (OR=2.16, p=3.0×10–10), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=–0.11, p=2.2×10–6) and more severe global psychopathology (beta=–0.16, p=4.7×10–6). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow‐up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research.

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Heterogeneity of Striatal Dopamine Function in Schizophrenia: Meta-analysis of Variance

Cited by 81 publications

References 71 publications

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

The clinical significance of duration of untreated psychosis: an umbrella review and random‐effects meta‐analysis

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