Dopamine genes and attention-deficit hyperactivity disorder: a review

OBJECTIVE: To review the results of genetic studies investigating dopamine-related genes in attention-deficit hyperactivity disorder (ADHD). DATA SOURCES: Papers (association/linkage, meta-analyses and animal model studies) were identified through searches of the PubMed database and systematically reviewed. DATA SYNTHESIS: Consistent results from molecular genetic studies are pointing strongly to the possible link between 2 specific genes, the dopamine transporter (SLC3A6) and the dopamine receptor 4 (DRD4), and ADHD. CONCLUSIONS: The implication of SLC6A3 and DRD4 genes in ADHD appears to be one of the most replicated in psychiatric genetics and strongly suggests the involvement of the brain dopamine systems in the pathogenesis of ADHD. However, more work is required to further these findings by genotype-to-phenotype correlations and identify the functional allelic variants/mutations that are responsible for these associations. The role of other dopamine genes, which may have smaller effects than SLC6A3 and DRD4, needs also to be determined.     

Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and a debilitating neuro-behavior disorder in the pediatric population. Although numerous effective psychostimulants are available, more than 30% of patients still do not show adequate treatment response rendering diverse pharmacological options. We aimed at assessing the efficacy and safety of modafinil in the treatment of children and adolescents with ADHD by conducting a meta-analysis. An extensive search of databases and clinical trial registries resulted in five published short-term randomized, double-blind, placebo-controlled trials. Primary efficacy measures were mean change in ADHD Rating Scale-IV Home (ADHD-RS-IV Home) and School Version (ADHD-RS-IV School) from baseline to study end point. The results showed that modafinil more significantly improved ADHD-RS-IV Home (SMD, −0.77 [95%CI, −1.11 to −0.44]) and School (SMD, −0.71 [95%CI, −0.96 to −0.47]) than placebo. Dropout rate due to adverse event did not significantly differ between two groups. In terms of commonly observed side effects, modafinil showed significantly higher incidence of decreased appetite (RR = 5.02, 95% CIs, 2.55 to 9.89, P < 0.00001) and insomnia (RR = 6.16, 95% CIs, 3.40 to 11.17, P < 0.00001). Modafinil did not cause a clinically significant increase of heart rate, systolic blood pressure, and diastolic blood pressure. Although we found that modafinil may be another treatment option in children and adolescents with ADHD, the results should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of clinical trials.     

A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder

OBJECTIVE: Meta-analysis was used to review the literature on the clinical use of clonidine to treat symptoms of attention-deficit hyperactivity disorder (ADHD). METHOD: A review of the literature from 1980 to 1999 revealed 39 studies that reported clonidine's efficacy and side effects for symptoms of ADHD and comorbid conditions. Of these, 11 reports provided sufficient information to be included in a meta-analysis. RESULTS: Meta-analysis using weighted variables revealed clonidine demonstrates a moderate effect size of 0.58 +/- 0.16 (95% confidence interval = 0.27-0.89) on symptoms of ADHD in children and adolescents with ADHD and ADHD comorbid with conduct disorder, developmental delay, and tic disorders. CONCLUSIONS: Clonidine may be an effective second-tier treatment for symptoms of ADHD, but it has an effect size less than that of stimulants. Clinical use of clonidine is associated with many side effects.     

Sleep in children with attention-deficit hyperactivity disorder: a meta-analysis of polysomnographic studies

The links between sleep and attention-deficit hyperactivity disorder (ADHD) have been a topic for intense ongoing research and clinical interest. Previous narrative literature reviews conveyed a consensus that parents of children with ADHD are more likely to report sleep problems in their children in comparison to parents of control children. However, when objective measures are considered the results appear to be more complex and inconsistent. This review is based on a meta-analysis of relevant polysomnographic studies. We assessed measures related to sleep architecture, breathing disorders, and periodic limb movements in sleep (PLMS), and the role of potential moderators such as age, gender, and other methodological factors. The meta-analysis revealed only one significant combined effect that indicates that children with ADHD are more likely than controls to suffer from PLMS. Factors such as age, gender, inclusion of adaptation night, and comorbidity appear to play a moderating role in the associations between sleep characteristics and ADHD. To provide new insight regarding the links between sleep and ADHD research in this field should adopt new strict guidelines and consider the role of multiple pertinent moderating factors.     

Age-related change of neurochemical abnormality in attention-deficit hyperactivity disorder: A meta-analysis

Prevalence and symptoms of attention-deficit hyperactivity disorder (ADHD) change with advancing age. However, neurochemical background of such age-related change is yet to be elucidated. We therefore conducted a meta-analysis of 16 proton magnetic resonance spectroscopy studies comprising 270 individuals with ADHD and 235 controls. Standardized mean differences were calculated and used as an effect size. Sensitivity analyses and meta-regression to explore the effect of age on neurochemical abnormality were performed. A random effects model identified a significantly higher-than-normal N-acetylaspartate (NAA) in the medial prefrontal cortex (mPFC), but no significant differences of other metabolites in that area. No significant difference in metabolite levels was demonstrated in any other region. Sensitivity analysis of children with ADHD revealed significantly higher-than-normal NAA, whereas no significant difference was found in adults with ADHD. Meta-regression revealed significant correlation between advanced age and normal levels of NAA in the mPFC, suggesting that age-dependent abnormality of NAA level in the mPFC is a potential neural basis of age-related change of symptoms of ADHD.     

Prevalence of attention-deficit/hyperactivity disorder in individuals with autism spectrum disorder: A meta-analysis

BackgroundComorbidity with attention-deficit/hyperactivity disorder (ADHD) is very common in autism spectrum disorder (ASD), worsening the developmental trajectory of ASD. The reported rates of ADHD in ASD vary widely. However, no meta-analysis has been conducted specifically to assess both the current and lifetime prevalence of ADHD in ASD. This study aims to fill in this gap.MethodWe searched the Web of Science, PubMed, PsycINFO, CINAHL, and Embase databases for eligible articles published between January 1, 2000, and September 5, 2020. The risk of bias tool was used to assess the studies’ quality. Overall pooled estimates of the current and lifetime prevalence of ADHD in ASD were obtained using random-effects models. Study heterogeneity was examined by Q and I² statistics.FindingsA total of 63 articles were eventually included, of which 56 studies reported the current prevalence, and 13 studies reported the lifetime prevalence. The results revealed that the pooled current and lifetime prevalence rates of ADHD among ASD were 38.5 % (95 % CI 34.0–43.2) and 40.2 % (95 % CI 34.9–45.7), respectively. Our study also confirmed that age, intellectual disability, recruitment settings, and diagnostic criteria significantly influenced the current prevalence of ADHD in ASD.ConclusionASD has considerable high current or lifetime prevalence rates of co-occurring ADHD. The findings demonstrate that clinicians should consider the high prevalence of ADHD in ASD and especially stay alert to possible ADHD diagnoses in school-age children and adolescents with ASD. Medical institutions should improve the assessment and tracking system of ADHD comorbidity in ASD and maximize the diagnostic accuracy for better treatment.     

Bupropion for adults with attention-deficit hyperactivity disorder: meta-analysis of randomized, placebo-controlled trials

Aim: The aim of this study was to systematically review the efficacy, acceptability and tolerability of bupropion in comparison to placebo. Only randomized‐controlled trials were included in the meta‐analysis. Methods: MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in October 2010. Study populations comprised adults with any subtype of attention‐deficit hyperactivity disorder, attention‐deficit disorder, hyperkinetic disorder, minimal brain dysfunction, minimal cerebral dysfunction or minor cerebral dysfunction. Efficacy outcomes were pooled mean changed scores of the ADHD rating scale (ADHD‐RS) and the overall response rates. The overall discontinuation rate was considered as the measure of acceptability. Results: A total of 349 participants (n for bupropion treatment = 175) in five published randomized, controlled trials were included. Bupropion sustained‐ or extended‐release was the experimental treatment in all studies. The pooled mean changed score of the ADHD‐RS of the bupropion‐treated group was greater than that of the placebo‐treated group with a weighted mean difference (95%CI) of 5.08 (3.13–7.03). The overall response rate of the bupropion‐treated group was significantly greater than that of placebo‐treated groups with a relative risk (95%CI) of 1.67 (1.23–2.26). However, the pooled overall discontinuation rate and the pooled discontinuation rate due to adverse events were not significantly different between groups with a relative risk (95%CI) of 1.11 (0.71–1.72) and 0.87 (0.08–9.79), respectively. Conclusion: The evidence suggests that bupropion is superior to placebo and effective for the treatment of ADHD in adults. However, its acceptability and tolerability were not significantly higher than those of placebo.     

Norepinephrine transporter and catecholamine-O-methyltransferase gene variants and attention-deficit/hyperactivity disorder symptoms in adults

Summary. Attention deficit/hyperactivity disorder (ADHD) is a complex, highly heritable psychiatric condition. Neuropsychological and pharmacological studies suggest a dysregulation of central noradrenergic neurotransmission in addition to dopaminergic and serotonergic mechanisms. Only a few studies have focused on the association of noradrenergic susceptibility genes with ADHD. In this study, we investigated the association of several ADHD symptom scores (German short form of the Wender Utah Rating Scale, WURS-k; ADHD self report, ADHD-SB, and the German validated version of the WRAADDS, WRI) with haplotypes of the catechol-O-methyltransferase (COMT) and the norepinephrine transporter (SLC6A2) genes. Subjects were genotyped for three SLC6A2 (rs5569, rs998424, rs2242447) and two COMT single nucleotide polymorphisms (rs4680, rs4818). In addition, psychosocial adversity in childhood was assessed in order to evaluate putative gene-environment interactions. We did not find main effects of the COMT and SLC6A2 NET1 gene haplotypes on any ADHD symptom severity score. Childhood psychosocial adversity was strongly associated with number of ADHD symptoms. No gene-environment interaction was found. A specific combination of two COMT and SLC6A2 gene haplotypes, containing the low functioning COMT variant was nominally associated with low ADHD scores in all scales. Results do not support the hypothesis that common variants in the SLC6A2 and COMT genes in particular are associated with ADHD, but might give some evidence for interactive effects between these gene variants on ADHD severity. Correspondence: Wolfgang Retz, Institute for Forensic Psychology and Psychiatry, Saarland University Hospital, 66421 Homburg/Saar, Germany     

Noninvasive brain stimulation in children and adults with attention-deficit/hyperactivity disorder: a systematic review and meta-analysis

BackgroundRepetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) could provide treatment alternatives to stimulant medication for attention-deficit/hyperactivity disorder (ADHD), given some evidence for improvements in cognition and clinical symptoms. However, despite a lack of solid evidence for their use, rTMS and tDCS are already offered clinically and commercially in ADHD. This systematic review and meta-analysis aimed to critically appraise rTMS and tDCS studies in ADHD to inform good research and clinical practice.MethodsA systematic search (up to February 2019) identified 18 studies (rTMS 4, tDCS 14; 311 children and adults with ADHD) stimulating mainly the dorsolateral prefrontal cortex (dlPFC). We included 12 anodal tDCS studies (232 children and adults with ADHD) in 3 random-effects meta-analyses of cognitive measures of attention, inhibition and processing speed.ResultsThe review of rTMS and tDCS showed positive effects in some functions but not others, and little evidence for clinical improvement. The meta-analyses of 1 to 5 sessions of anodal tDCS over mainly the left or bilateral dlPFC showed trend-level improvements in inhibition and processing speed, but not in attention.LimitationsHeterogeneity in stimulation parameters, patient age and outcome measures limited the interpretation of findings.ConclusionThe review and meta-analysis showed limited evidence that 1 to 5 sessions of rTMS and tDCS, mostly of the dlPFC, improved clinical or cognitive measures of ADHD. These findings did not support using rTMS or tDCS of the dlPFC as an alternative neurotherapy for ADHD as yet. Larger, multi-session stimulation studies identifying more optimal sites and stimulation parameters in combination with cognitive training could achieve larger effects.     

A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder

OBJECTIVE: To determine the empirical evidence for deficits in working memory (WM) processes in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: Exploratory meta-analytic procedures were used to investigate whether children with ADHD exhibit WM impairments. Twenty-six empirical research studies published from 1997 to December, 2003 (subsequent to a previous review) met our inclusion criteria. WM measures were categorized according to both modality (verbal, spatial) and type of processing required (storage versus storage/manipulation). RESULTS: Children with ADHD exhibited deficits in multiple components of WM that were independent of comorbidity with language learning disorders and weaknesses in general intellectual ability. Overall effect sizes for spatial storage (effect size = 0.85, CI = 0.62 - 1.08) and spatial central executive WM (effect size = 1.06, confidence interval = 0.72-1.39) were greater than those obtained for verbal storage (effect size = 0.47, confidence interval = 0.36-0.59) and verbal central executive WM (effect size = 0.43, confidence interval = 0.24-0.62). CONCLUSION: Evidence of WM impairments in children with ADHD supports recent theoretical models implicating WM processes in ADHD. Future research is needed to more clearly delineate the nature, severity, and specificity of the impairments to ADHD.     

The potential role of clock genes in children attention-deficit/hyperactivity disorder

BackgroundAttention deficit/ hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder and is thought to be associated with circadian system.MethodsWe performed a pathway-based study to test individual single nucleotide polymorphisms (SNPs) and the overall evidence of genetic polymorphisms involved in the circadian pathway in association with children ADHD susceptibility among a Chinese population. A community-based case–control study was conducted among Chinese children, and 168 ADHD patients and 233 controls were recruited using a combination diagnosis based on the diagnostic and statistical manual of mental disorders iv (DSM-IV) ADHD rating scale, Swanson, Nolan, and Pelham rating scale (SNAP-IV) rating scale, and semi-structured clinical interview.ResultsThe results of single-loci analyses identified that PER1 rs2518023 and ARNTL2 rs2306074 were nominally association with ADHD susceptibility (P < 0.05). Next, we applied multifactor dimensionality reduction (MDR), and classification and regression tree (CART) analyses to explore high-order gene–gene interactions among the functional SNPs to ADHD risks. The results indicated that interactions among the PER1 rs2518023, ARNTL2 rs2306074 and NR1D1 rs939347 were associated with the risk of ADHD in children. Individuals carrying the combination genotypes of the PER1 rs2518023 GG or GT, ARNTL2 rs2306074 TC or TT and NR1D1 rs939347 GA or AA displayed a significantly higher risk for ADHD than who carry the PER1 rs2518023 TT and CRY2 rs2292910 CA/CC genotypes (adjusted OR = 4.37, 95% CI = 2.16–8.85, P < 0.001).ConclusionsThese findings revealed the importance of genetic variations related to the circadian clock system to the susceptibility of children ADHD.     

Examining the relationship between obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in children and adolescents: a familial risk analysis.

BACKGROUND: To use family study methodology to examine the relationship between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. METHODS: We assessed for ADHD and OCD in the 1533 first-degree relatives of three groups of index children: those with ADHD and OCD, those with ADHD but no OCD, and matched controls with neither disorder. RESULTS: The risk for ADHD was similarly elevated in families of ADHD youth with (18.9%) and without OCD (20.1%; p = .91), and both groups had significantly higher rates of ADHD compared with controls (4.6%; p < or = .001), which was consistent with previous research showing a strong familial risk for ADHD. The risk for OCD was significantly elevated only among relatives of youth with ADHD plus comorbid OCD (13.0%) compared with controls (.5%; p < or = .001) and was consistent with previous research showing a strong familial risk for OCD. Relatives affected with ADHD had a significantly elevated risk for OCD compared with relatives unaffected by ADHD (7.4% vs. 1.3%; p < .001), suggestive of co-segregation between these disorders. There was no evidence of nonrandom mating between ADHD- and OCD-affected spouses. CONCLUSIONS: These results extend previously reported findings regarding the heritability of both ADHD and OCD and provide new evidence of a familial relationship between ADHD and pediatric OCD that best fits the hypothesis of a unique familial subtype.     

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.     

Revisiting the association between attention-deficit/hyperactivity disorder and anxiety disorders: a familial risk analysis.

BACKGROUND: This study tested competing hypotheses about patterns of familial association between attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders using familial risk analysis methodology. METHODS: The risk for ADHD and anxiety disorders in first-degree relatives was examined after stratifying ADHD probands by the presence or absence of comorbid anxiety disorders. The presence of anxiety disorders in probands and relatives was defined as meeting DSM-III-R diagnostic criteria for > or = 2 anxiety syndromes in the same subject. RESULTS: Familial risk analyses revealed that 1) the risk for anxiety disorders was significantly higher in ADHD probands and their relatives than in control probands and their relatives; 2) the risk for anxiety disorders among the relatives of ADHD probands was limited to those families in which the proband had a diagnosis of ADHD; 3) the risk for anxiety disorders was significantly higher among the relatives of ADHD probands with anxiety disorders than in relatives of ADHD probands without anxiety disorders, but these two groups did not differ in the familial risk for ADHD; and 4) ADHD and anxiety disorders did not cosegregate within families, and there was no evidence for nonrandom (assortative) mating. CONCLUSIONS: These findings are most consistent with the hypothesis that ADHD and anxiety disorders segregate independently in families.     

Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting 5-10% of school-age children. Although the biological basis of this disorder is unknown, twin and family studies provide strong evidence that ADHD has a genetic basis involving multiple genes. A previous study found an association between ADHD and two polymorphisms in the 3' untranslated region (UTR) of SNAP-25, a gene encoding a synaptic vesicle docking protein known to play a role in the hyperactivity observed in the Coloboma mouse strain. In this paper, we test biased transmission of the 3' UTR SNAP-25 haplotype using a larger ADHD sample of 113 families with 207 affected children. Using the transmission disequilibrium test (TDT), we found a trend consistent with biased transmission of the TC haplotype of SNAP-25 in all transmissions and detected a significant distortion (P=0.027) when paternal transmissions were evaluated.     

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample

Summary Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3′UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.