Evidence of sexual dimorphism of HTR1B gene on major adult ADHD comorbidities.

Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (Pcorr = 0.009 and Pcorr = 0.018, respectively) and for rs11568817 with nicotine dependence (Pcorr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorr = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.

Resilience to traumatic events related to urban violence and increased IL10 serum levels.

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 (CI95%); 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.

Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status.

BACKGROUND: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status. METHODS: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups. CONCLUSIONS: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.

Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the CHRNA5-CHRNA3-CHRNB4 gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors.

ADHD diagnosis may influence the association between polymorphisms in nicotinic acetylcholine receptor genes and tobacco smoking.

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster have been shown to be involved in tobacco smoking susceptibility. Considering that attention deficit/hyperactivity disorder (ADHD) not only increases the risk but may also influence the molecular mechanisms of tobacco smoking, we analyzed the association between polymorphisms in the nicotinic acetylcholine receptor genes and tobacco smoking among individuals with or without ADHD. The sample included 1,118 subjects divided into four groups according to smoking status and ADHD diagnosis. Our results demonstrate that the minor alleles of two polymorphisms (rs578776 and rs3743078) in the CHRNA3 gene are associated with an increased risk of tobacco smoking only among patients with ADHD. These alleles have been shown in previous studies to be protective factors for smoking in subjects without ADHD. These findings add to existing evidence that ADHD may exert an important modifying effect on the genetic risk of smoking and should be considered in tobacco smoking association studies.

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.

Smoking and ADHD: an evaluation of self medication and behavioral disinhibition models based on comorbidity and personality patterns.

OBJECTIVE: The prevalence of smoking is significantly increased among adults with Attention-Deficit/Hyperactivity Disorder (ADHD), and this association has a significant impact in both disorders, ascribed to either self-medication or behavioral disinhibition hypotheses. However, little is known about clinical variables associated with cigarette smoking among patients with ADHD. The present study evaluates comorbidity, demographic and personality profiles of patients with ADHD in relation to smoking status. METHODS: Patients (n422) were evaluated in the adult ADHD outpatient clinic of Hospital de Clínicas de Porto Alegre. Diagnoses were based on DSM-IV criteria and interviews were performed with Portuguese version of K-SADS-E for ADHD and Oppositional-Defiant Disorder. Axis I psychiatric comorbidities were evaluated with the SCID-I and smoking behavior with Fagerström Test for Nicotine Dependence (FTND). Personality was evaluated with Cloninger's Temperament and Character Inventory (TCI). RESULTS: The presence of smoking was strongly associated with externalizing characteristics as antisocial personality disorder (OR4.2) and substance dependence (OR6.5), but not with internalizing disorders. Moreover, smoking was associated with higher novelty seeking and lower harm avoidance scores. CONCLUSIONS: Smoking initiation among patients with ADHD is consistent with a behavioral disinhibition profile beyond the possible role of self-medication in smoking persistence. Smoking in these patients is strongly associated with externalizing comorbid disorders.

Smoking is associated with lower performance in WAIS-R Block Design scores in adults with ADHD.

Adults with attention-deficit/hyperactivity disorder (ADHD) are predisposed to smoking, but the neuropsychological correlates of this association have not been elucidated so far. The present study evaluates possible associations between cognitive performance and smoking and other comorbidities in adults with ADHD. Two hundred and sixty-four (264) patients were evaluated in the adult ADHD outpatient clinic of the Hospital de Clínicas de Porto Alegre. The diagnoses were based on the DSM-IV criteria and interviews were performed with the Portuguese version of K-SADS-E for ADHD and oppositional-defiant disorder. Axis I psychiatric comorbidities were evaluated with the SCID-IV and the cognitive performance with the Vocabulary and Block Design subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). The evaluation of the influence of the WAIS-R scores on each dependent variable was performed with logistic regression analyses. Lower scores in the Block Design subtest of WAIS-R were associated with smoking and the presence of anxiety disorder. These results suggest that a subgroup of ADHD patients with lower Block Design subtest scores may be at increased risk of smoking as a cognitive enhancement. Our findings also confirmed the previously suggested association between anxiety and lower Block Design scores.

Maus-tratos na infância: a importância e a compreensäo das dificuldades de sua detecçäo na escola / Child abuse: the importance and the comprehension of the difficulties of its detection in school

Os autores do presente trabalho enfatizam a importância da detecçäo dos maus-tratos nas crianças em instituiçöes escolares. Ressaltam, também, que isto näo é uma tarefa fácil, porém, uma abordagem multidisciplinar pode tornar factícel esta tarefa, assim como a valorizaçäo do papel do consultor escolar oriundo da área da Saúde Mental. Finalizam afirmando que somente o entendimento deste tema dentro da realidade sócio-econômica brasileira pode trazer algum resultado