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.

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.

The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD.

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5 % of school-aged children and 2.5 % of adults. Genetic studies in ADHD have pointed to genes in different neurobiological systems, with relatively small individual effects. The mineralocorticoid receptor is the main receptor involved in the initial triggering of stress response. Therefore, its encoding gene (NR3C2) is a candidate for psychiatric disorder studies, including ADHD, and behavioral phenotypes. There is evidence that the Val allele of the MRI180V polymorphism (rs5522) increases the risk of depression, attention and cognitive deficits. We investigated the possible role of the mineralocorticoid receptor gene in the symptom dimensions and susceptibility to persistent ADHD. We compared genotype and allele frequencies in 478 adult patients with ADHD and 597 controls and symptom dimensions in 449 patients and 132 controls. Diagnoses were based on the DSM-IV criteria. ADHD symptom dimensions were investigated with SNAP-IV for ADHD severity and Barkley scales for severity and impairment. Carriers of the Val allele presented higher inattention, hyperactivity/impulsivity and impairment scores, while genotype and allele frequencies did not differ between patients and controls. These results are consistent with a possible link between genetic variations in the HPA axis and inattention and hyperactivity measures.

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.

Response to methylphenidate is not influenced by DAT1 polymorphisms in a sample of Brazilian adult patients with ADHD.

Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region (3'-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3'-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3'-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.

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.

Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment.

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.

A haplotype analysis is consistent with the role of functional HTR1B variants in alcohol dependence.

BACKGROUND: Animal and human studies have suggested that the serotonergic system plays an important role in alcohol consumption and abuse, mainly due to the serotonin receptor 1B (5-HT(1B)) function in the mesolimbic reward pathway. Association studies between the HTR1B gene variants and alcoholism have found significant results. There is also evidence for a complex balancing regulation of the gene by two functional variants in the promoter region (rs11568817 and rs130058), which are in linkage disequilibrium. METHODS: The aim of this study is to investigate the role of the most relevant variants (rs11568817, rs130058, rs6296 and rs13212041) of the HTR1B gene in the susceptibility to alcohol dependence. The sample comprised 136 Brazilian alcoholics of European descendent and 237 controls. RESULTS: The results suggest an association between a functional variant of the gene (rs11568817) and alcohol dependence (p=0.001). In addition, this association could also be confirmed in an independent sample using imputed data from a GWAS, where marginal significant association (p=0.03, one-tailed) with the same allele was obtained. The pattern of distribution of haplotypes was significantly different between patients and controls (p<0.0001), which is consistent with the role of the two functional variants of the promoter region. CONCLUSION: In conclusion, our findings point to an association between functional variants in the promoter region of the HTR1B gene and alcohol dependence, supporting previous neurobiological evidences of the involvement of HTR1B variations in alcohol-related phenotypes.

Does age of onset of impairment impact on neuropsychological and personality features of adult ADHD?

The consideration of age of onset of impairment as part of the ADHD diagnosis is controversial and has been a revisited issue with the emergence of the new classifications in Psychiatry. The aim of this study is to compare patients with early and late onset of ADHD impairment in terms of neuropsychological and personality characteristics. Adult patients with ADHD (n = 415) were evaluated in the ADHD outpatient program at Hospital de Clínicas de Porto Alegre, Brazil. The diagnostic process for ADHD and comorbidities was based on DSM-IV criteria. The comparison between the two ages of onset groups (before 7; n = 209 or from 7 to 12 years; n = 206) was performed with ANOVA, followed by Stepwise forward regression analyses to restrict the number of comparisons and access the possible effect of multiple confounders. Patients with early onset ADHD present higher scores in novelty seeking in both analyses (respectively P = 0.016 and P = 0.002), but similar cognitive and attention features as compared with the late onset group. These data add to previous evidence that despite a more externalizing profile of early onset ADHD, the overall performance is similar reinforcing the need for awareness and inclusion of the late onset group in DSM-V diagnostic criteria.