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General Psychiatry 2019Evidence from clinical and preclinical studies has demonstrated that stress can cause depressive-like symptoms including anhedonia and psychomotor retardation, namely,...
BACKGROUND
Evidence from clinical and preclinical studies has demonstrated that stress can cause depressive-like symptoms including anhedonia and psychomotor retardation, namely, the manifestation of motivational deficits in depression. The proximate mediator of linking social-environmental stress with internal motivational deficits remains elusive, although substantial studies proposed neural endocrine mechanisms. As an endogenous danger-associated molecule, high mobility group box-1 (HMGB1) is necessary and sufficient for stress-induced sensitization of innate immune cells and subsequent (neuro)inflammation.
AIM
This review aims to provide evidence to unveil the potential mechanism of the relationship between motivational deficits and stress in depression.
METHODS
We reviewed original case-control studies investigating the association between HMGB1-mediated inflammation and stress-induced depression. The literature search of Pubmed and Web of Science electronic database from inception up to March 28th, 2019 were conducted by two independent authors. We performed a qualitative systematic review approach to explore the correlation between HMGB1-mediated inflammation and anhedonia/psychomotor retardation in depression.
RESULTS
A total of 69 studies based on search strategy were retrieved and seven eligible studies met the inclusion criteria. Studies showed that HMGB1 was implicated with depressive-like behaviors, which are similar with motivational deficits. Furthermore, HMGB1-mediated inflammation in depressive-like behaviors may be involved in Nod-like receptor family pyrin domain containing three (NLRP3) inflammasome and proinflammatory cytokines, abnormal kynurenine pathway and imbalance between neuroprotective and neurotoxic factors.
CONCLUSIONS
We found that stress-induced inflammation mediated by HMGB1 may affect motivational deficits through regulating dopamine pathway in corticostriatal neurocircuitry. The systematic review may shed light on the novel neurobiological underpinning for treatment of motivation deficits in depression.
PubMed: 31552388
DOI: 10.1136/gpsych-2019-100084 -
Medicine Sep 2019DRD2 TaqIA polymorphism may be associated with an increased risk of developing Parkinson disease (PD). However, the individual study's results are still inconsistent. (Meta-Analysis)
Meta-Analysis
BACKGROUND
DRD2 TaqIA polymorphism may be associated with an increased risk of developing Parkinson disease (PD). However, the individual study's results are still inconsistent.
METHODS
A meta-analysis of 4232 cases and 4774 controls from 14 separate studies were performed to explore the possible relationship between the DRD2 TaqIA gene polymorphism and PD. Pooled odds ratios (ORs) for the association and the corresponding 95% confidence intervals (CIs) were evaluated by a fixed-effect model.
RESULTS
The pooled results revealed a significant association between DRD2 gene TaqIA polymorphism under recessive genetic model (OR: 0.91, 95% CI:0.83,0.99, P = .031) and additive genetic models (OR:0.93,95%CI:0.87,0.99, P = .032), but not associated with PD susceptibility under other genetic models in the whole population. Moreover, subgroups based on ethnicity and genotyping methods showed this association in the Caucasian subgroup under recessive genetic model (OR: 0.85, 95% CI:0.76,0.95, P = .003) and additive genetic models (OR:0.87,95%CI:0.79,0.96, P = .004) were existed. Besides, no significant association was detected under 6 genetic models in the Asian populations and PCR-RFLP subgroup.
CONCLUSIONS
The current meta-analysis suggested that a significant association between DRD2 TaqIA polymorphism and PD under the recessive genetic mode, and additive genetic models, especially in Caucasians.
Topics: Genetic Predisposition to Disease; Humans; Parkinson Disease; Polymorphism, Genetic; Receptors, Dopamine D2
PubMed: 31517853
DOI: 10.1097/MD.0000000000017136 -
International Journal of Clinical... Oct 2019Cariprazine is an oral antipsychotic approved in the US for the treatment of schizophrenia, acute bipolar mania, and most recently, bipolar depression. The aim of this...
OBJECTIVE
Cariprazine is an oral antipsychotic approved in the US for the treatment of schizophrenia, acute bipolar mania, and most recently, bipolar depression. The aim of this systematic review is to describe the efficacy, tolerability and safety of cariprazine for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults.
DATA SOURCES
The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms "cariprazine" AND "bipolar" AND "depression," and by also querying the Web of Science commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.
STUDY SELECTION
Double-blind placebo-controlled studies in adults with bipolar depression.
DATA EXTRACTION
Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were calculated from the available study reports and other sources of information.
DATA SYNTHESIS
Cariprazine differs from other antipsychotics in that it has a 10-fold higher affinity for dopamine D3 receptors than for D2 receptors. Cariprazine's principal active metabolite, didesmethyl-cariprazine (DDCAR), has a half-life of 1-3 weeks and at steady state DDCAR is the predominant circulating moiety. Four double-blind placebo-controlled studies of cariprazine for bipolar depression were found of which three were considered positive and provided data on efficacy; all four studies were used to assess tolerability. Rates of treatment response, defined by a ≥50% reduction from baseline on the Montgomery-Asburg Depression Ratting Scale (MADRS) total score at study endpoint, for the approved doses of 1.5 and 3.0 mg/d (pooled) vs placebo were 46.3% vs 35.9% (NNT 10, 95% CI 7-21). Corresponding rates for remission (defined as MADRS total score ≤10 at endpoint) were 30.2% vs 20.9% (NNT 11, 95% CI 8-22). Discontinuation rates because of an adverse event (AE) were 6.7% for cariprazine (all doses pooled) vs 4.8% for placebo (NNH 51, ns). Product labelling lists the most common AEs as nausea, akathisia, restlessness and extrapyramidal symptoms. Patients receiving cariprazine 3.0 vs 1.5 mg/d were more likely to experience AEs and discontinue the trials because of an AE.
CONCLUSIONS
Cariprazine is the fourth agent approved for bipolar depression in the US. The likelihood to experience a benefit (response or remission) is substantially greater than the likelihood to encounter a discontinuation because of an AE. Direct, head-to-head comparisons with the other approved choices for bipolar depression in the "real world" are needed.
Topics: Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Double-Blind Method; Humans; Patient Selection; Piperazines; Treatment Outcome
PubMed: 31355510
DOI: 10.1111/ijcp.13397 -
Frontiers in Aging Neuroscience 2019The dopaminergic system has been associated with the progression of Alzheimer's disease. But previous studies found inconsistent results regarding the relationship...
The dopaminergic system has been associated with the progression of Alzheimer's disease. But previous studies found inconsistent results regarding the relationship between Alzheimer's disease and dopamine when looking at dopamine receptor concentrations. The aim of this review was to synthesize, using a random-effects model of meta-analysis, the link between the dopaminergic system and Alzheimer's disease. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42018110798). Electronic databases of PubMed, Embase, Web of Science, and Psyc-ARTICLES were searched up to December 2018 for studies that examined dopamine and dopamine receptors in relation to Alzheimer's disease. Standardized mean differences (SMD) were calculated to assess group differences in the levels of dopaminergic neurometabolites. Seventeen studies met the eligibility criteria. Collectively, they included 512 patients and 500 healthy controls. There were significantly lower levels of dopamine in patients with Alzheimer's disease compared with controls (SMD = -1.56, 95% CI: -2.64 to -0.49). In addition, dopamine 1 receptor (SMD = -5.05, 95% CI: -6.14 to -3.97) and dopamine 2 receptor (SMD = -1.13, 95% CI: -1.52 to -0.74) levels were decreased in patients with Alzheimer's disease compared with controls. The results of network meta-analysis indicated that the rank of correlation with Alzheimer's disease from highest to lowest was dopamine (0.74), dopamine 2 receptor (0.49), dopamine 3 receptor (0.46), dopamine 4 receptor (0.33), dopamine 5 receptor (0.31), and dopamine 1 receptor (0.64). Overall, decreased levels of dopaminergic neurotransmitters were linked with the pathophysiology of Alzheimer's disease. Nonetheless, there is a clear need for more prospective studies to validate these hypotheses.
PubMed: 31354471
DOI: 10.3389/fnagi.2019.00175 -
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 -
Addiction Biology May 2020Genetics account for moderate variation of individual differences in developing alcohol use disorder (AUD), but it is unclear which genetic variations contribute to AUD... (Meta-Analysis)
Meta-Analysis
Genetics account for moderate variation of individual differences in developing alcohol use disorder (AUD), but it is unclear which genetic variations contribute to AUD risk. One candidate gene investigated due to its association with AUD is the dopamine D4 receptor gene (DRD4), which contains a 48-base pair variable number tandem repeat (VNTR) in exon 3 of its coding region. To date, no quantitative synthesis of the published literature on the effects of DRD4 VNTR variation on alcohol-related phenotypes has been conducted. MEDLINE, Embase, Web of Science, and PsycInfo were searched for studies that reported on alcohol craving, alcohol consumption, severity of AUD, and case-control (AUD versus no diagnosis of AUD) studies in DRD4L (seven repeats or more) carriers compared with DRD4S (six repeats or less) homozygotes. Random-effects meta-analysis was used for all analyses. A pooled sample size of 655 to 13,360 of 28 studies were included. Compared with DRD4S homozygotes, DRD4L carriers had increased number of drinking days (SMD: 0.205; 95% CI: 0.008 to 0.402), binge drinking days (SMD: 0.217; 95% CI: 0.0532 to 0.380), and severity of AUD (SMD: 0.143; 95% CI: 0.028 to 0.259). There was no difference between DRD4 VNTR genotypes on drinks per drinking day, largest number of drinks per day/occasion, and case-control analysis. It was not possible to conduct a meta-analysis of the craving data, but a systematic review of this literature found mixed results on DRD4 VNTR genotype effect. The present meta-analysis suggests DRD4 VNTR variation may be a risk factor for problematic alcohol use. Our findings are limited, however, by the absence of ancestry data from studies included in our analysis, precluding our ability to adjust for population stratification. Due to the likelihood of type I error in candidate gene approaches, our work highlights the critical need for studies with larger and more inclusive samples that account for sex and genetic ancestry to fully understand this relationship.
Topics: Alcohol Drinking; Alcoholism; Binge Drinking; Craving; Humans; Minisatellite Repeats; Receptors, Dopamine D4
PubMed: 31149768
DOI: 10.1111/adb.12770 -
Eating and Weight Disorders : EWD Oct 2019To evaluate and understand the genetic and epigenetic basis of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD).
PURPOSE
To evaluate and understand the genetic and epigenetic basis of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD).
METHODS
The present systematic review was conducted in accordance to PRISMA guidelines. Advanced systematic searches of Medline, EMBASE, PsychINFO, Web of Science, Scopus, CINHAL plus, and the Cochrane Library were conducted using the search terms 'bulimia nervosa', 'bulimia spectrum disorder', 'borderline personality disorder', 'genes', and 'genetics'. The search strategy garnered seven studies for inclusion in the present review.
RESULTS
Women with BN/BSD-BPD had significantly lower serotonin and monoamine oxidise activity compared to women with BN/BSD or healthy controls (HC). As well, women with BN/BSD-BPD displayed elevated methylation of the dopamine receptor gene promoter, brain-derived neurotrophic factor, and changes in the methylation of the glucocorticoid receptor gene promoter (NR3C1) compared to women with BN/BSD and HC. The results also demonstrated that rates of childhood sexual abuse and childhood physical abuse are higher in those with BN/BSD-BPD than those with BN/BSD and HC, and that these types of abuse are often correlated with the methylation differences seen in BN/BSD-BPD women.
CONCLUSION
Due to the differences observed between individuals with BN/BSD-BPD and those with BN/BSD and HC a genetic/epigenetic aetiological model of BN/BSD-BPD was developed and is proposed in this review. This evidence-based model visually illustrates the current state of the field and draws attention to the need for subsequent research.
Topics: Adult Survivors of Child Abuse; Borderline Personality Disorder; Bulimia; Bulimia Nervosa; Epigenesis, Genetic; Humans
PubMed: 31119586
DOI: 10.1007/s40519-019-00688-7