Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability.

Impulsivity, a multifaceted behavioral hallmark of attention-deficit/hyperactivity disorder (ADHD), strongly influences addiction vulnerability and other psychiatric disorders that incur enormous medical and societal burdens yet the neurobiological underpinnings linking impulsivity to disease remain poorly understood. Here we report the critical role of ventral striatal cAMP-response element modulator (CREM) in mediating impulsivity relevant to drug abuse vulnerability. Using an ADHD rat model, we demonstrate that impulsive animals are neurochemically and behaviorally more sensitive to heroin and exhibit reduced Crem expression in the nucleus accumbens core. Virally increasing Crem levels decreased impulsive action, thus establishing a causal relationship. Genetic studies in seven independent human populations illustrate that a CREM promoter variant at rs12765063 is associated with impulsivity, hyperactivity and addiction-related phenotypes. We also reveal a role of Crem in regulating striatal structural plasticity. Together, these results highlight that ventral striatal CREM mediates impulsivity related to substance abuse and suggest that CREM and its regulated network may be promising therapeutic targets.

Comorbidity in adults with attention-deficit/hyperactivity disorder.

This paper describes the clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) in adulthood, with particular emphasis placed on issues relating to comorbidity. Prospective and retrospective studies are reviewed to evaluate the degree to which adults with ADHD exhibit clinical features that mirror their childhood counterparts with analogous comorbid psychiatric (e.g., antisocial, mood, and anxiety) and/or cognitive (i.e., learning) disorders. We also address the question of whether comorbid disorders in adults represent independent diagnostic entities and whether the presence of psychiatric comorbidity varies as a function of ADHD subtype (i.e., inattentive, hyperactive-impulsive, combined, and residual). As is the case for ADHD in childhood, comorbidity is not uncommon among adults with ADHD. However, the reported prevalence of comorbid conditions among adults with ADHD varies considerably depending upon whether the research used a prospective or retrospective design.

ADHD, aggression, and antisocial behavior across the lifespan. Interactions with neurochemical and cognitive function.

The progression to adult antisocial behavior is the least desirable developmental trajectory for children with ADHD. An unremitting pattern of physical aggression appears of great import when predicting long-term outcome. However, a profile characterized by behavioral and cognitive impulsivity and emotional lability may indicate a greater likelihood of the progression to adult antisocial behavior and violent impulse-control disorders. This constellation of behaviors appears to be, at least in part, mediated by brain serotonergic systems. The contribution of cognitive impairments, as manifested by executive function deficits, diminished moral reasoning, and impaired empathic ability, to the emergence and persistence of antisocial behavior has yet to be discerned.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

Relationship between central serotonergic function and aggression in prepubertal boys: effect of age and attention-deficit/hyperactivity disorder.

Data indicate that diminished central serotonergic (5-HT) function is related to aggression in adults, but discrepant findings in children suggest that age or the presence of attention-deficit/hyperactivity disorder (ADHD) may influence this relationship. This study examined whether age or ADHD affects the association between 5-HT and aggression in 7-11-year old clinically-referred boys. Forty-six boys were divided into non-aggressive ADHD, aggressive ADHD, and aggressive non-ADHD groups based on responses to interviews and ratings of behavior. Central 5-HT function was assessed by measuring the prolactin response to a 1-mg/kg oral dose of D,L-fenfluramine. There was no significant difference in the prolactin response across the three groups of boys. Furthermore, when examined dimensionally, prolactin response was largely unrelated to ratings of aggression, even after controlling for ADHD. Finally, age was not associated with prolactin response, and had no effect on the relationship between prolactin response and aggression. This study provides further evidence that there is no clear relationship between central 5-HT function and aggression in disruptive boys. Moreover, these data do not confirm the hypothesis that age or the presence of ADHD influence the relationship between 5-HT and childhood aggression.

Serotonin and aggression in children.

Research consistently indicates that in animals and adults, reduced central serotonergic (5-HT) function is associated with increased aggression. This relationship has been elucidated via cerebrospinal fluid monoamine metabolite levels, hormonal responses to pharmacologic challenge using serotonergic probes, platelet receptor binding studies, and, more recently, through molecular genetic approaches. In contrast, studies examining the relationship of 5-HT to aggression in children have been characterized by inconsistent findings. The literature examining the relationship between central 5-HT function and aggression is reviewed. Several hypotheses that might account for the discrepancies in the child literature are examined.

The neurobiology of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder is a childhood psychiatric disorder characterized by inattention, impulsivity, and overactivity. Considerable research has focused on the neurobiological substrates of this disorder. Although the specific nature of the brain dysfunction remains elusive, progress has been made and several models of the underlying pathophysiology have been suggested. Research in the fields of neuropsychology, neuroimaging, neurochemistry, and molecular genetics, which points to a multifactorial etiology for the disorder, is reviewed. While several inconsistencies exist across studies, evidence supports dysfunction of fronto-striatal dopaminergic and noradrenergic circuits with resultant executive deficits in cognitive functioning.

Parent-teacher concordance for DSM-IV attention-deficit/hyperactivity disorder in a clinic-referred sample.

OBJECTIVE: To examine concordance between parent and teacher reports of DSM-IV attention-deficit/hyperactivity disorder (ADHD) and its symptoms. METHOD: Parents and teachers of 74 clinically referred children were interviewed using the ADHD module of the Diagnostic Interview Schedule for Children. Parent-teacher agreement for the diagnosis of ADHD and its subtypes, as defined in DSM-IV, as well as parent-teacher concordance of in-school ADHD symptoms, was examined. RESULTS: Agreement between parents and teachers was found to be relatively poor, with virtually no agreement for individual ADHD subtypes. Diagnoses based on either parent or teacher report frequently yielded a diagnosis of either inattentive or hyperactive-impulsive subtype of ADHD. However, when cross-informant data were used to form diagnoses, these subtypes became relatively rare, with most cases meeting criteria for ADHD combined type. In addition, parent reports of in-school behavior were more highly correlated with their own reports of their child's behavior at home than with teacher reports of their child's behavior in school. CONCLUSIONS: These data suggest that the diagnosis of ADHD inattentive or hyperactive-impulsive subtype based on data from a single informant may be of questionable validity, and they point to the importance of using multiple informants when diagnosing this disorder in clinically referred samples.

ADHD and reading disabilities: a cluster analytic approach for distinguishing subgroups.

Data suggest that children with reading disability (RD) and non-RD children with attention-deficit/hyperactivity disorder (ADHD) may comprise distinct subgroups. Research has been hampered by variance in definitional criteria, which results in the study of different subgroups of children. Using cluster analysis, this study empirically divided children with ADHD (N = 54), based on their Full Scale IQ (FSIQ) and reading ability. Four distinct subgroups emerged in which cognitive, behavioral, and neurochemical function was compared. Cluster 1 was of average FSIQ and reading scores; Cluster 2 was of average FSIQ but showed impairment in reading; Cluster 3 had high FSIQ and reading scores; and Cluster 4 had low scores in both domains. The groups had different patterns of cognitive, behavioral, and neurochemical function, as determined by discrepancies in Verbal-Performance IQ, academic achievement scores, parent aggression ratings, and a measure of noradrenergic function. These distinctions are discussed with regard to etiology, treatment, and long-term outcome.

Neurobiological models of attention-deficit/hyperactivity disorder: a brief review of the empirical evidence.

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, impulsivity, and overactivity that begins in childhood. While considerable research has focused on the neurobiological substrates of this disorder, the specific nature of the brain dysfunction in ADHD has remained elusive. However, early data from pharmacological treatment studies, as well as from basic research in animals and humans, initially led several investigators to develop neurobiological models of ADHD. These models of ADHD and more recent evidence from neuropsychological, neuroimaging, neurochemical, and genetic research are briefly reviewed. While not completely consistent, the empirical data suggest that dysfunction in prefrontal-striatal neural circuits, as well as in brain stem catecholamine systems that innervate these circuits, may underlie the executive function deficits in ADHD.

Predictors of physical aggression in children with attention-deficit/hyperactivity disorder.

The present investigation examined factors that predict physical aggression in children with attention-deficit/hyperactivity disorder (ADHD). Stepwise, multiple regression-analyses were used to examine predictors of children's physical aggression as rated by parents at a 1-year follow-up point and by teachers at both 1- and 2-year follow-up points. Early parent and teacher ratings of verbal aggression (ie, cursing, teasing, and threatening) accounted for the greatest proportion of the variance in physical aggression ratings obtained at follow-up. None of the other predictor variables, including early ratings of physical aggression and ADHD behaviors, contributed significant additional variance beyond that accounted for by early verbal aggression ratings. Temporal and cross-informant analyses revealed that the relationship between verbal aggression and later physical aggression was situation-specific for teacher ratings but not parent ratings. Although physical aggression may emerge early in development, these data suggest that verbal aggression represents a stable, temperamental characteristic that may be of greater value than early physical aggression for predicting later physically aggressive acts.

Neurocognitive functioning in adults with attention-deficit/hyperactivity disorder.

The performance of nine adults with attention-deficit/hyperactivity disorder (ADHD) was compared with the performance of 23 normal controls on computerized measures of target orientation, sustained attention, encoding speed, and motor output/response organization to determine the nature of the neurocognitive deficits of adults with ADHD. While the groups' performances on measures of sustained attention and encoding speed did not differ, significant group differences were seen on a task that targeted motor output/response organization. These data suggest that the neurocognitive difficulties of ADHD adults are not related to a primary deficit in sustained attentional functioning. Rather, the deficient information processing in ADHD adults is related to difficulties with motor output/response organization.

Thermal response to serotonergic challenge and aggression in attention deficit hyperactivity disorder children.

Body temperature change in response to the serotonergic (5-HT) enhancer, d,l-fenfluramine (FEN), was examined in 27 prepubescent boys diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) to determine (1) the utility of this measure as an index of central serotonergic function; and (2) if the magnitude of temperature change is associated with aggression. FEN, 1 mg/kg, produced a significant increase in body temperature, the magnitude of which was correlated with plasma levels of the FEN metabolite, norfenfluramine (NORFEN). Furthermore, a significant inverse relationship was found between temperature response to FEN and teacher ratings of aggression. Parent ratings of aggression were not significantly correlated with the hyperthermic response to FEN. Interestingly, the magnitude of the hyperthermic response was unrelated to changes in plasma levels of prolactin and cortisol, suggesting that thermal and neuroendocrine responses are mediated by distinct 5-HT mechanisms. The agreement of these finding with those of studies using other procedures to assess the relationship between 5-HT and aggression suggests that decreased central 5-HT is associated with increased aggression.

Identification of AD/HD subtypes using laboratory-based measures: a cluster analysis.

The current investigation used laboratory-based measures of inattention, impulsivity, and activity level to identify subgroups of children with attention-deficit/hyperactivity disorder (AD/HD). Data derived from solid state actigraphs and a continuous performance test (CPT) were obtained from a clinically referred sample and submitted to a cluster analysis. These empirically derived groups were then evaluated for clinical relevance and subsequently validated by parent and teacher ratings and tests of intellectual functioning and academic achievement. Four distinct subgroups emerged: Hyperactive-inattentive (HYP-IN), impulsive-inattentive (IMP-IN), inattentive only, and hyperactive only. The HYP-IN group was impaired on measures of intellectual functioning and academic achievement relative to the other three groups. In contrast, the IMP-IN group was generally rated as more aggressive, although this difference was not statistically significant for all measures. The data suggest that the augmentation of clinical descriptors with laboratory-based data may be an effective strategy by which to categorize diagnostic subgroups of AD/HD.

Stimulant medications.

OBJECTIVE: To review the short- and long-term safety and efficacy of stimulants for the treatment of children with attention-deficit/hyperactivity disorder (ADHD). METHOD: A Medline search was conducted for both randomized controlled trials and reviews to determine the efficacy and safety of stimulant drugs for treating children with ADHD. Information was obtained on adverse events associated with their use, including their impact on height and weight gain during childhood. Animal data were reviewed for information on tolerance, sensitization, and the impact of high-dose stimulant effects on neurons and on the development of hepatic tumors. Human data on dopamine transporter occupancy by stimulants were also included. RESULTS: Stimulant treatment studies show robust short-term efficacy and a good safety profile. Longer-term studies are few in number but have produced no conclusive evidence that careful therapeutic use of these medications is harmful. CONCLUSION: Current evidence indicates that stimulants show efficacy and safety in studies lasting up to 24 months.

A longitudinal study of neurobiological mechanisms in boys with attention-deficit hyperactivity disorder: preliminary findings.

BACKGROUND: The stability and developmental variation of several neurobiological measures in boys with attention-deficit hyperactivity disorder (ADHD) were examined. METHODS: The prolactin (PRL) response to fenfluramine (FEN) challenge was used to assess central serotonergic (5-HT) functioning in 10 8-11-year-old boys with ADHD. In addition, platelet 5-HT, as well as plasma levels of the catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid were ascertained. These neurobiological variables were reassessed in the same children 2-3 years later using the identical procedures. RESULTS: The PRL response to FEN challenge was the only measure found to be stable across the evaluations (r = .58), although the magnitude of the response decreased significantly with age. Plasma MHPG level significantly increased with age. CONCLUSIONS: Central 5-HT function, as measured by the PRL response to FEN, may represent a stable trait. The importance of considering developmental factors when interpreting neurobiological data is discussed.

Psychological testing for child and adolescent psychiatrists: a review of the past 10 years.

OBJECTIVE: To provide a review of psychological tests often used with children and adolescents. METHOD: A description of how psychological tests are used and how to interpret various types of scores is provided. Subsequently, psychological tests used to assess intelligence, academic achievement, neuropsychological functions, and personality are reviewed. RESULTS: There are numerous well-normed, reliable, and valid instruments that are available for assessing intellectual and academic functioning in children and adolescents. Neuropsychological tests, designed to assess objectively a wide range of cognitive functions, are available and extremely useful for designing treatment plans for patients with cognitive difficulties. Despite their popularity, most projective tests have relatively weak psychometric data supporting their reliability and/or validity. CONCLUSIONS: Psychological testing provides objective measures of behavior that are of considerable utility for evaluating children and adolescents. However, psychological test data, in isolation, will rarely be adequate for providing a DSM diagnosis, and test scores are best interpreted in the context of other clinical data. Psychological test data can be very useful for developing a comprehensive treatment plan that addresses the patient's cognitive and emotional needs.

Serotonin function and risk for alcoholism in boys with attention-deficit hyperactivity disorder.

Data in animals and adults indicate that central serotonergic (5-HT) function may be involved in the development of alcohol abuse. Despite this, studies exploring this mechanism in individuals at risk for alcoholism are scant. This study used a fenfluramine (FEN) challenge procedure to investigate the relationship between risk for alcoholism and 5-HT function in 7- to 11-year-old boys with attention-deficit hyperactivity disorder (ADHD). The prolactin (PRL) and cortisol (CORT) responses to FEN were examined in 10 sons of alcoholic fathers (FA+) and 30 sons of nonalcoholic fathers (FA-). The FA+ group had a significantly greater CORT, but not PRL, response to FEN relative to the FA- group. The discrepancy between the CORT and PRL responses may be due to the different mechanisms that underlie their 5-HT stimulated release. This suggests that, among ADHD boys, those at familial risk for alcohol abuse may differ from those who are not at risk in 5-HT function.

Alpha 2 adrenergic agonists. Neurochemistry, efficacy, and clinical guidelines for use in children.

The alpha 2 adrenergic agonists are used to treat a variety of psychiatric disorders and their usage has been increasing. This article presents the rationale and neurochemical basis for treatment of psychiatric disorders with alpha 2 agents, reviews studies examining clinical efficacy, and develops guidelines for usage. Case vignettes are presented to illustrate how the alpha 2 agents can successfully be used in practice.

Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension.

OBJECTIVE: To examine noradrenergic (NA) function in children with attention-deficit hyperactivity disorder (ADHD) by replicating and expanding upon a previous finding that ADHD children with and without reading disabilities (RD) differ in plasma levels of the NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). METHOD: Plasma levels of MHPG were compared in ADHD children who were subdivided on the basis of the presence or absence of RD. Subsequently, this replication sample was combined with a previously studied sample to further explore the relationship between plasma MHPG levels and measures of cognitive function in children with ADHD. RESULTS: Plasma levels of MHPG were significantly lower in ADHD children without RD, compared with those with RD, replicating a published finding. Analyses in the combined sample indicated that, among children with ADHD, plasma MHPG levels were inversely associated with measures of academic achievement and verbal processing, but not parent or teacher ratings of behavior or continuous performance test measures of attention and impulsivity. CONCLUSIONS: These data indicate that children with ADHD are not homogeneous with regard to NA function and that neurochemical variation is closely associated with differences in clinical characteristics of the children.