There is an increasing body of knowledge on the influence of differential DNA methylation of specific genomic regions in psychiatric disorders. However, fewer studies have addressed global DNA ...methylation (GMe) levels. GMe is an estimative of biological functioning that is regulated by pervasive mechanisms able to capture the big picture of metabolic and environmental influences upon gene expression. In the present perspective article, we highlighted evidence for the relationships between cortisol and sex hormones and GMe in psychiatric disorders. We argue that the far-reaching effects of cortisol and sexual hormones on GMe may lie on the pathways linking stress and mental health. Further research on these endocrine-epigenetic links may help to explain the role of environmental stress as well as sex differences in the prevalence of psychiatric disorders.
Attention-deficit/hyperactivity disorder (ADHD) is traditionally conceptualized as a neurodevelopmental disorder that continues into adulthood in up to half of diagnosed cases. In light of current ...evidence, factors associated with the course of the disorder remain unknown. We performed a systematic review of the literature searching for risk markers from childhood that predicted the persistence of ADHD into adulthood. We reviewed 26,168 abstracts and selected 72 for full-text review. We identified data from 16 studies, comprising 6 population-based retrospective samples and 10 clinical follow-ups. We performed meta-analyses of factors evaluated by at least three studies. Severity of ADHD (OR 2.33, 95 % CI = 1.6–3.39,
p
< 0.001), treatment for ADHD (OR 2.09, 95 % CI = 1.04–4.18,
p
= 0.037), comorbid conduct disorder (OR 1.85, 95 % CI = 1.06–3.24,
p
= 0.030), and comorbid major depressive disorder (OR 1.8, 95 % CI = 1.1–2.95,
p
= 0.019) emerged as predictors already presented in childhood for ADHD persistence into adulthood. Further, we suggest that cohort studies should be designed to clarify such an important question for research and clinical practice.
Abstract The exposition to traumatic events related to urban violence is epidemic in Brazil, with rate of 80% in the general population, and is becoming a major cause of post-traumatic stress ...disorder (PTSD). The objective of the study was to compare serum levels of pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10) in PTSD and resilient individuals. We hypothesized that resilient individuals present an attenuated pro-inflammatory and enhanced anti-inflammatory state. We conducted a case-control study comparing 30 resilient individuals and 30 PTSD patients exposed to traumatic events related to urban violence. The groups were evaluated using Self-Report Questionnaire (SRQ-20), Mini-International Neuropsychiatric Interview (MINI) and the Davidson Trauma Scale. For all individuals, blood samples were collected to determine IL-6, IL-10 and cortisol serum levels. All samples were frozen at –80 °C until the assay and were analyzed with the same immunoassay kit and in duplicates. The resilient group presented higher IL-10 levels than PTSD patients mean (CI); 1.03 (0.52–2.08) pg/mL vs. 0.29 (0.20–0.43) pg/mL; P = 0.002. There were no differences in terms of IL-6 or cortisol levels. The results provided evidence for increased levels of IL-10 in resilient individuals when compared to PTSD patients, probably conferring them a better anti-inflammatory response after exposition.
Antisocial and criminal behaviors are multifactorial traits whose interpretation relies on multiple disciplines. Since these interpretations may have social, moral and legal implications, a constant ...review of the evidence is necessary before any scientific claim is considered as truth. A recent study proposed that men with wider faces relative to facial height (fWHR) are more likely to develop unethical behaviour mediated by a psychological sense of power. This research was based on reports suggesting that sexual dimorphism and selection would be responsible for a correlation between fWHR and aggression. Here we show that 4,960 individuals from 94 modern human populations belonging to a vast array of genetic and cultural contexts do not display significant amounts of fWHR sexual dimorphism. Further analyses using populations with associated ethnographical records as well as samples of male prisoners of the Mexico City Federal Penitentiary condemned by crimes of variable level of inter-personal aggression (homicide, robbery, and minor faults) did not show significant evidence, suggesting that populations/individuals with higher levels of bellicosity, aggressive behaviour, or power-mediated behaviour display greater fWHR. Finally, a regression analysis of fWHR on individual's fitness showed no significant correlation between this facial trait and reproductive success. Overall, our results suggest that facial attributes are poor predictors of aggressive behaviour, or at least, that sexual selection was weak enough to leave a signal on patterns of between- and within-sex and population facial variation.
•MPH increased attentional and mnemonic performances in the SHR.•MPH decreased impulsive behavior of the SHR.•MPH had no effect on hyperactivity.•Our results do not fully support the predictive ...validity of SHR as an ADHD model.
The spontaneously hypertensive rats (SHR) are the most widely used model for ADHD. While face and construct validity are consolidated, questions remain about the predictive validity of the SHR model. We aim at summarizing the evidence for the predictive validity of SHR by evaluating its ability to respond to methylphenidate (MPH), the most well documented treatment for ADHD. A systematic review was carried out to identify studies evaluating MPH effects on SHR behavior. Studies (n=36) were grouped into locomotion, attention, impulsivity or memory, and a meta-analysis was performed. Meta-regression, sensitivity, heterogeneity, and publication bias analyses were also conducted. MPH increased attentional and mnemonic performances in the SHR model and decreased impulsivity in a dose-dependent manner. However, MPH did not reduce hyperactivity in low and medium doses, while increased locomotor activity in high doses. Thus, since the paradoxical effect of stimulant in reducing hyperactivity was not observed in the SHR model, our study does not fully support the predictive validity of SHR, questioning their validity as an animal model for ADHD.
Abstract The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in ...mineralocorticoid and glucocorticoid receptor genes ( NR3C2 and NR3C1 , respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes.
Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of ...specific findings. In this sense, the
CHRNA5
gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of
CHRNA5
variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The
CHRNA5
SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG,
P
= 0.032; CC,
P
= 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 p
global-corrected
= 7.66 × 10
–5
) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction—in line with the expected effects of cocaine in the cholinergic system—and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating
CHRNA5
with the genetics and pathophysiology of addiction of different drugs.
The dopamine transporter (SLC6A3/
DAT1
) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for ...attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3′-untranslated region (UTR) of the
DAT1
, but these investigations have reported heterogeneous findings. The few studies focused on the 5′ region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the −839 C/T (rs2652511) promoter variant and the 3′-UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (
P
= 0.002) between the rs2652511 C-allele with ADHD. In addition, the 6-repeat allele of Int8 VNTR was associated with higher inattention scores (
P
= 0.034). The haplotype analysis including
DAT1
3′-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of
DAT1
as a risk factor for ADHD susceptibility.
Abstract Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion ...of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were ‘ADHD’, ‘Attention-Deficit/Hyperactivity Disorder’ and ‘gene’ in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene ( DAT1 ) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD.
PDF
