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European Archives of Psychiatry and... Aug 2021The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and... (Meta-Analysis)
Meta-Analysis
The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and genetics in the databases of Pubmed, Scopus, Cochrane Library and PsycINFO, and performed a meta-analysis when appropriate. We evaluated 111 articles, of which 25 were finally included in the analysis. The studies were assessed by two independent researchers for methodological quality using the Downs and Black Tool and for genetic analysis quality. We performed a meta-analysis of 10 studies of the Apolipoprotein E (APOE) gene, obtaining no association with the presence of delirium (LOR 0.18, 95% CI - 0.10-0.47, p = 0.21). Notably, only 5 out of 25 articles met established criteria for genetic studies (good quality) and 6 were of moderate quality. Seven studies found an association with APOE4, the dopamine transporter gene SCL6A3, dopamine receptor 2 gene, glucocorticoid receptor, melatonin receptor and mitochondrial DNA haplotypes. One genome-wide association study found two suggestive long intergenic non-coding RNA genes. Five studies found no association with catechol-o-methyltransferase, melatonin receptor or several interleukins genes. The studies were heterogenous in establishing the presence of delirium. Future studies with large samples should further specify the delirium phenotype and deepen our understanding of interactions between genes and other biological factors.
Topics: Delirium; Genetic Predisposition to Disease; Humans
PubMed: 33779822
DOI: 10.1007/s00406-021-01255-x -
Behavioural Pharmacology Sep 2012Anorexia nervosa (AN) is a chronic relapsing psychiatric disorder with a largely unknown pathophysiology. Dopamine has been implicated in the pathophysiology of the... (Review)
Review
Anorexia nervosa (AN) is a chronic relapsing psychiatric disorder with a largely unknown pathophysiology. Dopamine has been implicated in the pathophysiology of the disorder by preclinical and clinical evidence. Preclinical studies have examined two main characteristics of AN: reduction in food intake (diet restriction) and hyperactivity. Diet restriction has been associated with reduced dopamine levels in the hypothalamus, hippocampus, and the dorsal striatum. Animal hyperactivity following diet restriction has been linked to increased dopamine in the hypothalamus. Increased dopamine in the nucleus accumbens was associated with food administration, but not food expectation. Tyrosine and dopaminergic antagonists normalized anorexia-like behaviors in animal models of AN, but did not restore body weight. Clinical studies on the etiology of AN have produced contradictory findings. Cerebrospinal fluid concentrations of dopamine and its metabolites have been reported to be decreased or normal under conditions of low weight, whereas they tended to normalize when the weight was restored. Plasma and urinary levels of dopamine and its metabolites have been found to be normal, increased, and decreased. Neuroendocrine studies suggest that dopaminergic neurotransmission is increased in AN. However, recent neuroimaging studies lend support to the increase in binding of dopaminergic receptors in the striatum, which favors the opposite theory that intrasynaptic dopamine is indeed decreased. Genetic studies implicate dopamine D2 receptors, the dopamine transporter, and the enzyme COMT. There are promising results with respect to the use of atypical antipsychotics against symptoms of AN beyond weight gain, but further trials are required.
Topics: Animals; Anorexia Nervosa; Antidepressive Agents; Catechol O-Methyltransferase; Depression; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Plasma Membrane Transport Proteins; Humans; Neuroendocrine Cells; Organ Specificity; Polymorphism, Genetic; Receptors, Dopamine D2; Synaptic Transmission
PubMed: 22854306
DOI: 10.1097/FBP.0b013e328357e115 -
Biological Psychiatry Oct 2019Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.
METHODS
We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.
RESULTS
We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.
CONCLUSIONS
Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
Topics: Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Polymorphism, Single Nucleotide; Receptors, Dopamine
PubMed: 31303260
DOI: 10.1016/j.biopsych.2019.05.014 -
Molecular Psychiatry May 2024The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social...
The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social stressors increases psychosis risk, possibly by upregulating striatal dopamine functioning. Here we systematically review single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies that examined the relationship between chronic social stress exposure and in vivo striatal dopamine functioning in humans. We searched the scientific databases PubMed and PsycINFO from inception to August 2023. The quality of the included studies was evaluated with the ten-item Observational Study Quality Evaluation (PROSPERO: CRD42022308883). Twenty-eight studies were included, which measured different aspects of striatal dopamine functioning including dopamine synthesis capacity (DSC), vesicular monoamine transporter type 2 binding, dopamine release following a pharmacological or behavioral challenge, D receptor binding, and dopamine transporter binding. We observed preliminary evidence of an association between childhood trauma and increased striatal DSC and dopamine release. However, exposure to low socioeconomic status, stressful life events, or other social stressors was not consistently associated with altered striatal dopamine functioning. The quality of available studies was generally low. In conclusion, there is insufficient evidence that chronic social stressors upregulate striatal dopamine functioning in humans. We propose avenues for future research, in particular to improve the measurement of chronic social stressors and the methodological quality of study designs.
PubMed: 38760501
DOI: 10.1038/s41380-024-02581-x -
Neuroscience and Biobehavioral Reviews Dec 2020Dopamine has a crucial and well-documented role in the development and maintenance of Gambling Disorder (GD). This systematic review adopts a translational approach... (Review)
Review
Dopamine has a crucial and well-documented role in the development and maintenance of Gambling Disorder (GD). This systematic review adopts a translational approach aimed at providing a comprehensive synthesis of current clinical and preclinical knowledge on dopaminergic function in GD at a neurobiological level. To this end, we present and discuss converging dopaminergic alterations and phenotypes. Preclinical and clinical review protocols were registered on the PROSPERO database (CRD42019124404, CRD42019124405). The literature search was conducted in accordance with PRISMA guidelines using three databases (PubMed, Web of Science, Scopus). We identified 67 preclinical studies using pharmacological and non-pharmacological manipulations of the gambling-like phenotype and 33 human studies investigating either genetic polymorphisms or functional brain imaging data. Dopamine transporter and D2, D3, D4 receptor alterations showed strongest translational concordance. Though no postsynaptic dopaminergic alterations were observed, several studies point at dysfunctions in presynaptic dopamine trafficking in GD, suggestive of hyperdopaminergic states. Developing meaningful translational models is essential to working towards the development of an integrated conceptual framework for GD and neurobiologically-based treatment interventions.
Topics: Dopamine; Gambling; Humans
PubMed: 33035523
DOI: 10.1016/j.neubiorev.2020.09.034 -
Neuropsychopharmacology : Official... Mar 2019Use of alcohol, cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs. The exact pathophysiology of abuse or... (Meta-Analysis)
Meta-Analysis
Use of alcohol, cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs. The exact pathophysiology of abuse or addiction associated with these sedative substances is not completely understood, but previous research implicates the important role of the striatal dopamine system in the addiction process. Multiple studies investigated changes in the striatal dopamine systems of users of sedative substances, but currently these results are very heterogeneous. Therefore, we conducted a meta-analysis of in vivo neuroimaging studies investigating dopaminergic alterations in the striatum of users of alcohol, opioids or cannabis. Analyses for each substance were conducted separately for the availability of D2/D3 dopamine receptors, dopamine transporters and dopamine synthesis capacity. In total, 723 substance users and 752 healthy controls were included. The results indicated a significant lower striatal D2/D3 receptor availability in alcohol users compared to controls (g = 0.46) but no difference in dopamine transporter availability or dopamine synthesis capacity. Our analysis indicated that changes of dopamine receptors and transporters are moderated by the duration of abstinence. Comparing opioid users with controls revealed a significant lower D2/D3 receptor availability (g = 1.17) and a significantly lower transporter availability (g = 1.55) in opioid users. For cannabis users, there was no significant difference in receptor availability compared to controls and too few studies provided information on dopamine transporter availability or synthesis capacity. Our analysis provides strong evidence for a central role of the striatal dopamine system in use of alcohol or opioids. Further studies are needed to clarify the impact of the dopamine system in cannabis users.
Topics: Alcoholism; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Humans; Marijuana Abuse; Neuroimaging; Opioid-Related Disorders; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 30188512
DOI: 10.1038/s41386-018-0191-9 -
Obesity Reviews : An Official Journal... Nov 2023This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed... (Review)
Review
Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies.
This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for C-raclopride, F-fallypride, I-IBZM; one for dopamine transporter, I-FP-CIT; one used tracer for serotonin 5-HT receptor, F-altanserin; two used tracers for serotonin transporter, C-DASB or I-FP-CIT; two used tracer for μ-opioid receptor, C-carfentanil; one used tracer for noradrenaline transporter, C-MRB); seven studies assessed glucose uptake using F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using O-H O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using F-FTHA and one using C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.
Topics: Humans; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; Bariatric Surgery; Brain; Obesity; Neurotransmitter Agents
PubMed: 37699864
DOI: 10.1111/obr.13620 -
Movement Disorders : Official Journal... Aug 2021Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine... (Meta-Analysis)
Meta-Analysis Review
Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta-analysis of the available PET and single-photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single-photon emission computed tomography imaging; dopamine receptor tracers (D1-like or D2-like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2-like studies had 1925 patients. Data were insufficient for an analysis of D1-like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA-P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist-induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Parkinson Disease; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon
PubMed: 33955044
DOI: 10.1002/mds.28632 -
Neuroscience and Biobehavioral Reviews Nov 2019A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder....
A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder. Paradoxically, blockade of mu-opioid receptors (MORs) intended to suppress dopamine release and alcohol reward is a widely used treatment for preventing relapse in alcohol use disorder (AUD). To elucidate this apparent discrepancy, we systematically survey the literature on experimental studies in AUD subjects and animal models, which assessed striatal dopamine levels and D1, D2-like receptor, dopamine transporter and MOR via positron emission tomography (PET) and ex vivo receptor binding assays. The reported evidence indicates a changing dopaminergic signaling over time, which is associated with concomitant alterations in MOR, thus suggesting a highly dynamic regulation of the reward system during abstinence. Such a view can reconcile the various evidences from in vivo and postmortem studies, but makes developing an effective pharmacological intervention that specifically targets either dopamine receptors or the transporter system a daunting task.
Topics: Alcoholism; Animals; Autopsy; Craving; Humans; Positron-Emission Tomography; Receptors, Dopamine; Receptors, Opioid, mu; Reward
PubMed: 30243576
DOI: 10.1016/j.neubiorev.2018.09.010 -
Sexual Medicine Reviews Oct 2020A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature...
INTRODUCTION
A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature ejaculation (PE); however, the results remain inconclusive.
OBJECTIVES
This systematic review aimed: (i) to determine whether an association exists between gene(s) or allelic variant(s) and PE; (ii) to assess whether the associations are consistent across studies in magnitude and direction, and (iii) to identify any limitation, gap, or shortcoming in the included studies.
METHODS
The literature search was conducted in PubMed, MEDLINE, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases.
RESULTS
Different gene variants associated with PE were assessed. 25 genetic association studies met the inclusion criteria that investigated 11 genes, 2,624 men with PE compared with 9,346 men as controls, twins, and siblings. 19 studies demonstrated a significant association with PE, whereas 4 studies denied such a relationship. SLC6A4 gene polymorphism was investigated in 11 studies (7 studies demonstrated a significant relationship with PE, and 4 studies denied such a relationship). Dopamine transporter gene (DAT1) polymorphism was investigated in 4 studies exhibiting a significant relationship. Androgen receptor gene polymorphisms were investigated in 2 studies, 1 with a significant relationship and the other with a non-significant relationship. Oxytocin gene polymorphisms and tryptophan hydroxylase 2 gene polymorphisms were investigated in 2 studies with a significant relationship.
CONCLUSION
While this review has highlighted several genes that may be potentially associated with PE such as SLC6A4, limitations such as variance in study methods, lack of robust findings, small sample sizes, lack of reproducibility, quality of reporting, and quality of assessment remain a major concern. Further efforts such as standardizing reporting, exploring complementary designs, and the use of genome-wide association studies technology are warranted to test the reproducibility of these early findings. Mostafa T, Abdel-Hamid IA, Taymour M, et al. Gene Variants in Premature Ejaculation: Systematic Review and Future Directions. Sex Med Rev 2020;8:586-602.
Topics: Dopamine Plasma Membrane Transport Proteins; Genetic Association Studies; Humans; Male; Oxytocin; Polymorphism, Genetic; Premature Ejaculation; Receptors, Androgen; Receptors, Serotonin; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 32800770
DOI: 10.1016/j.sxmr.2020.07.002