The neuropsychopharmacology of attention-deficit/hyperactivity disorder.

More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.     

Rodent models of attention-deficit/hyperactivity disorder.

An ideal animal model should be similar to the disorder it models in terms of etiology, biochemistry, symptomatology, and treatment. Animal models provide several advantages over clinical research: simpler nervous systems, easily interpreted behaviors, genetic homogeneity, easily controlled environment, and a greater variety of interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of childhood onset that is characterized by inattentiveness, hyperactivity, and impulsiveness. Its diagnosis is behaviorally based; therefore, the validation of an ADHD model must be based in behavior. An ADHD model must mimic the fundamental behavioral characteristics of ADHD (face validity), conform to a theoretical rationale for ADHD (construct validity), and predict aspects of ADHD behavior, genetics, and neurobiology previously uncharted in clinical settings (predictive validity). Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD. Poor performers in the five-choice serial reaction time task and Naples high-excitability rats (NHE) are useful models for attention-deficit disorder. Other animal models either focus on the less important symptom of hyperactivity and might be of limited value in ADHD research or are produced in ways that would not lead to a clinical diagnosis of ADHD in humans, even if ADHD-like behavior is displayed.     

Genetics of adult attention-deficit/hyperactivity disorder.

Results of behavioral genetic investigations using family twin and adoption studies converge with those of molecular genetic studies in showing that genes influence susceptibility to'attention-deficit/hyperactivity disorder (ADHD). These finding suggest that genetic mechanisms that predispose individuals to ADHD are complex. It seems likely that the disorder is caused by the combined actions of several genes. It is equally clear that aberrant genes create a vulnerability to the disorder that is not expressed in all environments. The literature about the genetics of adult ADHD is relatively small, but it suggests not only that the persistent form of ADHD is familial, but that it is more familial than the nonpersistent form.More work from twin and molecular genetic studies is needed to determine if the increased familiality of persistent ADHD reflects the actions of genes or of familial environmental causes.     

Molecular genetics of attention-deficit/hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.     

Zinc in attention-deficit/hyperactivity disorder

OBJECTIVE: The aim of this study was to review the published evidence for a role of zinc nutrition in attention-deficit/hyperactivity disorder (ADHD). METHOD: A computer literature search was supplemented by the authors' knowledge. RESULTS: Numerous controlled studies report cross-sectional evidence of lower zinc tissue levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal controls and population norms. A few studies show correlations of zinc level with either clinical severity or a change thereof in response to stimulant or chemical challenge. Two placebo-controlled trials--one of zinc monotherapy, the other of zinc supplementation of methylphenidate--reported significant benefit. However, diagnostic procedures and sample representativeness were often not clear, and most such reports have come from countries and cultures with different diets and/or socioeconomic realities than are found in the United States (only one American sample in nine published reports). In particular, both positive clinical trials of zinc supplementation came from the Mid-East (Turkey and Iran), an area with suspected endemic zinc deficiency. The largest of these trials used zinc doses above the recommended upper tolerable limit and had a 2 in 3 dropout rate. CONCLUSION: It is not clear how well the accumulating evidence for a possible role of zinc in ADHD applies to middle-class American children. However, the evidence appears strong enough to warrant further controlled study in well-diagnosed samples representative of the socioeconomic spectrum. Hypothesis-testing clinical trials are needed of this potential treatment that, if found effective, might become a relatively safe, cheap substitute for, or adjunct to, current treatments in some patients. At present, it should remain an investigational treatment.     

Inattentiveness in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a long-term impact on functioning, productivity and quality of life of patients. This impact is largely due to the symptoms of inattentiveness. However, despite its impairing role in the lives of ADHD patients, inattentiveness has been studied relatively less frequently than have symptoms of impulsivity/hyperactivity and problems with executive function. This review therefore seeks to integrate the neuropsychological theories and current findings in the research fields of neuropsychology, neurophysiology, and neuroimaging, in an attempt to gain a more complete understanding of the role that inattentiveness plays in ADHD, as well as to suggest directions for future studies. The need for a more comprehensive understanding of inattentiveness and ADHD, which integrates findings from each of the three disciplines mentioned above, is emphasized.     

Structural brain imaging of attention-deficit/hyperactivity disorder.

Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study (Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.     

Stimulant treatment of adult attention-deficit/hyperactivity disorder.

Though only recently recognized as a valid disorder in adults, the clinical picture of adult ADHD is highly reminiscent of childhood ADHD,with continued associated occupational failure and academic deficits. Similarly, many adults with ADHD suffer from antisocial, depressive, and anxiety disorders. Recent work clearly documents that when therapeutic doses of MPH and amphetamine treatment are used in the treatment of adults with ADHD, they can lead to a robust clinical response that is highly consistent with that observed in pediatric studies using equipotent daily doses. As in childhood ADHD, medication remains a key component of treatment for adults with ADHD. More studies are needed to evaluate the efficacy and safety of stimulants over the long-term and their impact on quality of life.     

The dopamine transporter and attention-deficit/hyperactivity disorder.

The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.     

Age-dependent expression of attention-deficit/hyperactivity disorder symptoms.

The authors' research indicates that most adults with ADHD continue to struggle with substantial number of ADHD symptoms and high levels of dysfunction despite a sizable syndromatic remission. Furthermore, in-attention was more persistent than hyperactivity or impulsivity as children progress throughout adolescence and into early adulthood. These results stress the critical importance of carefully choosing the appropriate definition of remission in longitudinal studies of youth with ADHD and that symptom clusters and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined ADHD subtypes (ie, combined, inattentive., or hyperactive/'impulsive) should be considered separately.     

Sleep disorders and attention-deficit/hyperactivity disorder

The relationship between attention-deficit/hyperactivity disorder (ADHD) and sleep is complex and poses many challenges in clinical practice. Recent studies have helped to elucidate the nature of the neuromodulator systems underlying the associations among sleepiness, arousal, and attention. Studies of sleep disturbances in children with academic and behavioral problems have also underscored the role that primary sleep disorders play in the clinical presentation of symptoms of inattention and behavioral dysregulation. Recent research has shed further light on the prevalence, type, risk factors for, and impact of sleep disturbances on children with ADHD. The following discussion of the multilevel and bidirectional relationships among sleep, neurobehavioral functioning, and the clinical syndrome of ADHD synthesizes current knowledge about the interaction of sleep and attention/arousal in these children. Guidelines are provided to outline a clinical approach to evaluating and managing children with ADHD and sleep problems.     

Update on adult attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and highly morbid neurobehavioral disorder afflicting children, adolescents, and adults throughout the world. This article discusses the clinical assessment of adult ADHD, reviews the results of recent adult ADHD treatment studies with an emphasis on medications currently approved by the US Food and Drug Administration, and discusses the clinical management and monitoring of ADHD pharmacotherapy.     

College students with attention-deficit/hyperactivity disorder

As more students with attention-deficit/hyperactivity disorder attend college, studies are emerging that reveal problems in psychosocial and academic functioning. Substance use may magnify deficits in self-regulation. Recommendations are made for comprehensive assessment; however, the usual diagnostic categories may not be developmentally relevant. Students who are identified benefit from medication and nonmedication interventions, strategy support, and accommodations.     

Psychosocial treatments for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a chronic disorder requiring developmentally sensitive interventions across the lifespan. Although pharmacotherapy traditionally has been considered the first-line treatment for ADHD, many individuals continue to experience significant functional impairment or choose not to pursue pharmacotherapy. Thus, evidence-based alternatives or adjuncts to pharmacologic treatment for individuals with ADHD are needed. Behavioral parent training and behavioral school interventions are the only empirically supported nonpharmacologic interventions for children and adolescents with ADHD. This article reviews recent additions to the ADHD literature, including evaluations of behavioral interventions in traditional clinical practice and schools, treatment efficacy for preschool-aged children and adults, and the investigation of a novel treatment for individuals with the predominantly inattentive subtype of ADHD.     

Genetic aspects in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.     

Impulsive behaviors in attention-deficit/hyperactivity disorder

The notion that difficulty in behavioral inhibition is the essential impairment of attention-deficit/hyperactivity disorder (AD/HD) has been prevailing. In this study, we assessed impulsive behaviors with regard to emotion, rule, and inattentiveness, by developing an impulsiveness scale and applying it for 103 parents of a boy with AD/HD. Exploratory factor analysis (EFA) of 18 items identified four primary factors: labeled emotion expression, social rule, rule in conversation, and inattentiveness. A covariance structural analysis was performed to extract response bias from latent constructs, and the fitness of the model was examined. In the finally adopted model on impulsive behaviors, the four factors extracted in EFA was explained by two independent second-order latent variables: labeled general impulsivity and cognitive impairment. Cognitive impairment significantly influenced on inattentiveness only, while general impulsivity on all the four factors. Furthermore, the scores of primary four factors were compared between two groups of a normal class group (n = 20) and three AD/HD subtypes:combined type (n = 37), predominantly hyperactive-impulsive type (n = 14), and predominantly inattentive type (n = 18). The results suggest differences in impulsive behaviors among the AD/HD subtypes.