Global DNA methylation patterns in Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a highly prevalent condition worldwide that produces a wide range of pathophysiological consequences, with a critical impact on health and social issues. Alcohol influences gene expression through epigenetic changes mainly through DNA methylation. In this sense, levels of 5-methylcytosine (5-mC), namely Global DNA methylation (GMe), which can be influenced by environmental and hormonal effects, represent a putative biological mechanism underlying alcohol effects. Our aim was to investigate the influence of AUD diagnosis and alcohol patterns (i.e., years of addiction, use in the last 30 days, and alcohol severity) on GMe levels. The sample consisted of 256 men diagnosed with AUD and 361 men without AUD. DNA samples from peripheral blood were used to assess GMe levels, measured through the levels of 5-mC using high-performance liquid chromatography. Results from multiple linear regression analysis indicated that the presence of AUD was associated with lower GMe levels (beta=-0.155, p=0.011). Other alcohol-related outcomes were not associated with DNA methylation. Our findings are consistent with the hypothesis that the impact of chronic and heavy alcohol use in GMe could be a potential mechanism mediating the multiple organ damages related to AUD.

Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores.

Genetic and environmental factors contribute to the etiology of Attention Deficit-Hyperactivity Disorder (ADHD). In this sense, the study of epigenetic mechanisms could contribute to the understanding of the disorder's neurobiology. Global DNA methylation (GMe) evaluated through 5-methylcytosine levels could be a promising epigenetic biomarker to capture long-lasting biological effects in response to environmental and hormonal changes. We conducted the first assessment of GMe levels in subjects with ADHD (n = 394) and its main comorbidities in comparison to populational controls (n = 390). Furthermore, given the high genetic contribution to ADHD (heritability of 80%), polygenic risk scores (PRS) were calculated to verify the genetic contribution to GMe levels in ADHD and the comorbidities associated with GMe levels. The GMe levels observed in patients were lower than controls (P = 1.1e-8), with women being significantly less globally methylated than men (P = 0.002). Regarding comorbidities, the presence of bipolar disorder (BD) among patients with ADHD was associated with higher methylation levels compared to patients with ADHD without BD (P = 0.031). The results did not change when pharmacological treatment was accounted for in the analyses. The ADHD and BD most predictive PRSs were negatively (P = 0.0064) and positively (P = 0.0042) correlated with GMe, respectively. This study is the first to report an association between GMe, ADHD, and its comorbidity with BD and associations between PRSs for specific psychiatric disorders and GMe. Our findings add to previous evidence that GMe may be a relevant piece in the psychiatric disorders' etiological landscape.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

The role of glucocorticoid receptor gene in the association between attention deficit-hyperactivity disorder and smaller brain structures.

ADHD is associated with smaller subcortical brain volumes and cortical surface area, with greater effects observed in children than adults. It is also associated with dysregulation of the HPA axis. Considering the effects of the glucocorticoid receptor (NR3C1) in neurophysiology, we hypothesize that the blurred relationships between brain structures and ADHD in adults could be partly explained by NR3C1 gene variation. Structural T1-weighted images were acquired on a 3 T scanner (N = 166). Large-scale genotyping was performed, and it was followed by quality control and pruning procedures, which resulted in 48 independent NR3C1 gene variants analyzed. After a stringent Bonferroni correction, two SNPs (rs2398631 and rs72801070) moderated the association between ADHD and accumbens and amygdala volumes in adults. The significant SNPs that interacted with ADHD appear to have a role in gene expression regulation, and they are in linkage disequilibrium with NR3C1 variants that present well-characterized physiological functions. The literature-reported associations of ADHD with accumbens and amygdala were only observed for specific NR3C1 genotypes. Our findings reinforce the influence of the NR3C1 gene on subcortical volumes and ADHD. They suggest a genetic modulation of the effects of a pivotal HPA axis component in the neuroanatomical features of ADHD.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Feasibility trial of the dialectical behavior therapy skills training group as add-on treatment for adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: Our aim was to explore the feasibility, and efficacy of a Dialectical Behavior Therapy Skill Training Group (DBT-ST) as an add-on treatment for adult attention-deficit/hyperactivity disorder (ADHD) in Latin America. METHOD: Adults with ADHD (n = 31) with stable medication treatment for ADHD and residual symptoms (ASRS > 20) were randomly assigned to DBT-ST (n = 16) or treatment as usual (TaU; n = 15) for 12 weeks. Feasibility was accessed by attendance and completion rates at 12 weeks. Efficacy outcomes were measured with the ASRS, and performed at 0, 6, 12, and 16 weeks. RESULTS: The DBT-ST protocol had 81.25% completion rate, with a mean attendance of 87.25% of the sessions. No significant interactions between group and time were detected for outcome measures. DISCUSSION: The DBT-ST was feasible as add-on treatment for adult patients with ADHD in Latin America. Replicating previous findings, DBT-ST has shown no significantly higher improvement in ADHD symptoms in comparison with TaU. Registered at the Clinical Trials database (NCT03326427).

Effects of DRD2 splicing-regulatory polymorphism and DRD4 48 bp VNTR on crack cocaine addiction.

There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2-DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48 bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2-DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2-DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.

Attention-deficit hyperactivity disorder in ancient Greece: The Obtuse Man of Theophrastus.

We present an ancient Greek description written by the philosopher Theophrastus in his classic book ' Characters' comparable with modern attention-deficit hyperactivity disorder. The arguments are based in one chapter of this book-The Obtuse Man-presenting features of a character closely resembling the modern description of attention-deficit hyperactivity disorder. In a free comparative exercise, we compared Theophrastus descriptions with modern Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) attention-deficit hyperactivity disorder symptoms. The sentences describing The Obtuse Man written by Theophrastus are similar to several symptoms of attention-deficit hyperactivity disorder and he would probably be currently diagnosed with this disorder as an adult. To our knowledge, this is the oldest description compatible with the current conception of attention-deficit hyperactivity disorder in adults in the Western literature. Differently than the moralistic view of ancient Greece regarding those symptoms, the medical attention-deficit hyperactivity disorder conception may be advantageous to patients since it might reduce prejudice and allow individuals to seek treatment.

Predictors of persistence of ADHD into adulthood: a systematic review of the literature and meta-analysis.

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.

Reliability and Validity of Proposed DSM-5 ADHD Symptoms in a Clinical Sample of Adults.

The DSM-5 ADHD and Disruptive Behaviors Work Group proposed two major changes for diagnosis of attention deficit hyperactivity disorder (ADHD) in adults: (1) inclusion of four new impulsivity symptoms and (2) reduction in the number of symptoms required for assigning an ADHD diagnosis. In this case-control study, the performance of these modifications was assessed in a clinical sample of 133 adult subjects (68 ADHD cases and 65 non-ADHD control subjects). The proposed new impulsivity symptoms for adults do not improve ADHD diagnosis enough to overcome potential negative effects of changing the criteria. However, fewer symptoms than the six-of-nine threshold required by DSM-IV provided the best cutoff point for identifying adults who are impaired.

NCAM1-TTC12-ANKK1-DRD2 gene cluster and the clinical and genetic heterogeneity of adults with ADHD.

Dysfunctions of the dopaminergic system have been implicated on the etiology of Attention Deficit/Hyperactivity Disorder (ADHD). Meta-analyses addressing the association of the dopamine receptor D2 (DRD2) gene and ADHD were inconclusive due to excessive heterogeneity across studies. Both the great phenotypic heterogeneity of ADHD and the complexity of the genomic region where DRD2 is located could contribute to the inconsistent findings. Most previous DRD2 studies focused on the well-known Taq1A (rs1800497) SNP, which is actually placed in a neighbor gene (ANKK1). These two genes, together with NCAM1 and TTC12, form the NTAD gene cluster on Chr11q22-23. In order to address the reasons for the high heterogeneity previously reported on DRD2 effects on ADHD, this study investigates the role of NTAD variants on ADHD susceptibility in adults and on the modulation of comorbidity and personality profiles in these patients. Functional polymorphisms from NTAD were analyzed, both individually and in haplotypes, on a sample of 520 adults with ADHD and 630 non-ADHD controls. No direct association of NTAD variants with ADHD susceptibility itself was observed. However, different NTAD polymorphisms and haplotypes were associated to various phenotypes relevant to the clinical heterogeneity of ADHD, including Major Depressive Disorder, Generalized Anxiety Disorder, and Harm Avoidance and Persistence temperament scores. Therefore, these findings represent a possible explanation for the multiple conflicting findings regarding polymorphisms in this genomic region in psychiatry. The NTAD cluster may comprise a variety of independent molecular influences on various brain and behavior characteristics eventually associated with ADHD comorbidities and personality traits. © 2015 Wiley Periodicals, Inc.

Severity but not comorbidities predicts response to methylphenidate in adults with attention-deficit/hyperactivity disorder: results from a naturalistic study.

Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P < 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.

Could comorbid bipolar disorder account for a significant share of executive function deficits in adults with attention-deficit hyperactivity disorder?

OBJECTIVE: The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD. METHODS: Adult patients with ADHD and healthy subjects were evaluated in the ADHD outpatient Program at the Hospital de Clínicas de Porto Alegre. Psychiatric diagnoses were based on DSM-IV criteria. WCST scores were compared by multivariate analysis of covariance among three groups: ADHD with BD (n = 51), ADHD without BD (n = 278), and healthy subjects (n = 91). RESULTS: When compared to patients without BD and healthy subjects, patients with ADHD and comorbid BD showed lower scores in total correct answers (p = 0.003); higher scores in total errors (p = 0.004) and non-perseverative errors (p = 0.002); and completed fewer categories (p = 0.009). Patients with ADHD without BD did not differ from healthy subjects. CONCLUSIONS: WCST impairments among patients with ADHD seem to be to a large extent attributable to comorbid BD. Although other executive function deficits (e.g., in the inhibitory control domain) have been demonstrated to accompany ADHD, the present findings suggest that set-shifting deficits are strongly related to comorbid BD.

Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults.

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.

Glutamatergic copy number variants and their role in attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762-1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066-3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631-9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals.

Prevalence and associated factors of burnout among health sciences students in Spain - a systematic review.

BACKGROUND: There is growing concern about the occurrence burnout syndrome in university students worldwide. This systematic review aimed to estimate the prevalence of burnout syndrome and its associated factors among health sciences students (HSS) from Spain. METHODS: Five databases (MEDLINE/PubMed, PsycINFO, EMBASE, Dialnet and MEDES) were searched up to January 5, 2023, adhering to PRISMA guidelines. Quantitative studies reporting the prevalence of burnout syndrome among HSS from Spanish universities were considered. The reference lists of the selected studies were hand searched. Data were extracted from peer-reviewed articles. RESULTS: Twenty-six studies with a total of 14,437 HSS were included (11 nursing, 8 Medicine, five Psychology, two Dentistry, one Physiotherapy, one Pharmacy students). Overall, study quality was fair. The most widely used instrument was the Maslach Burnout Inventory. The mean prevalence of burnout was 35.3% (k=11 studies). However, rates varied widely across the studies, which may result from methodological differences. Inconsistent associations were found with gender and year of study. The relationship of burnout with academic-and mental-health related variables was consistent across studies. Personal attributes such as higher resilience, are likely protective from burnout. CONCLUSIONS: Burnout seems to be prevalent among HSS in Spain, and can be affected by academic, mental health-related and personality factors. The identification of risk and protective factors of burnout could help develop preventive and management strategies, to ultimately reduce its negative consequences in this population.

MR and GR functional SNPs may modulate tobacco smoking susceptibility.

A number of studies have demonstrated that stress is involved in all aspects of smoking behavior, including initiation, maintenance and relapse. The mineralocorticoid (MR) and glucocorticoid (GR) receptors are expressed in several brain areas and play a key role in negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis. As nicotine increases the activation of the HPA axis, we wondered if functional SNPs (single nucleotide polymorphisms) in MR and GR coding genes (NR3C2 rs5522 and NR3C1 rs6198, respectively) may be involved in smoking susceptibility. The sample included 627 volunteers, of which 514 were never-smokers and 113 lifetime smokers. We report an interaction effect between rs5522 and rs6198 SNPs. The odds ratio (OR) for the presence of the NR3C2 rs5522 Val allele in NR3C1 rs6198 G carriers was 0.18 (P = 0.007), while in rs6198 G noncarriers the OR was 1.83 (P = 0.027). We also found main effects of the NR3C1 rs6198 G allele on number of cigarettes smoked per day (P = 0.027) and in total score of the Fagerström Test for Nicotine Dependence (P = 0.007). These findings are consistent with a possible link between NR3C2 and NR3C1 polymorphisms and smoking behavior and provide a first partial replication for a nominally significant GWAS finding between NR3C2 and tobacco smoking.

Theophrastus's Anaisthetos Transdiagnostic Presentation: comment on Pehlivanidis and Papanikolaou (2022).

We were pleased to read Pehlivanidis and Papanikolaou's article1 and see that more colleagues are recognizing Theophrastus' text as the first description of Attention Deficit Hyperactivity Disorder (ADHD).2 We agree with the authors' perspective that Theophrastus' description may suggest the presence of more than one neurodevelopmental disorder. In fact, Theophrastus' description aligns with the shared clinical symptoms and underlying neurodevelopmental mechanisms of ADHD and Social Pragmatic Communication Disorder (SPCD). It is fascinating that a description from over 2000 years ago already presented prototypical individual transdiagnostic aspects that are compatible with a modern biological view of psychiatry. Indeed, it is not unexpected that heritable traits with clear biological underpinnings should have been perceived since the dawn of medicine. A significant leap forward in the development of this field came a few decades ago when Clements (1966)3 published a NIH-sponsored project entitled 'Minimal Brain Dysfunction in Children.' This seminal work prepared the terrain for the ongoing understanding of the grouping of signs, symptoms, and biological factors observed across various neurodevelopmental disorders. This grouping can be present in different spectrums, proportions, and nuances, including children and adults with some impairments that are not solely explained by their cognitive abilities. Thus, the characterization of 'The Obtuse Man' by Theophrastus could be considered a prototypical case of this more integrated and less fragmented view of what we call neurodevelopmental disorders.

No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD.

Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.