Individuals with attention deficit hyperactivity disorder (ADHD) smoke at rates significantly higher than the general population and have more difficulty quitting than nondiagnosed individuals. Currently, there are no evidence-based approaches for reducing smoking specifically in individuals with ADHD. Adult regular smokers with or without ADHD participated in a study of extended smoking withdrawal where monetary incentives were used to promote abstinence. Participants were paid according to an escalating schedule for maintaining abstinence measured as self-report of no smoking and an expired air carbon monoxide (CO) level of ≤4 parts per million. Sixty-four percent (14/22) of smokers with ADHD and 50% (11/22) of smokers without ADHD maintained complete abstinence for the 2-week duration of the study. Twenty-two percent (5/22) and 9% (2/22) of smokers with ADHD and without ADHD, respectively, maintained continued abstinence for up to 10 days following the removal of the contingencies. Though abstinence rates were higher for the smokers with ADHD, the group differences were not statistically significant. Results suggest that monetary incentives may be a useful approach for promoting abstinence in adult smokers with ADHD, perhaps owing to altered reinforcement processes in these individuals.

Introduction:

Initial reactions to cigarettes predict later regular smoking. Symptoms of attention deficit hyperactivity disorder (ADHD) have also been shown to increase smoking risk and may moderate the relationship between genotype and smoking. We conducted an exploratory study to assess whether ADHD symptoms interact with genetic variation to predict self-reported initial reactions to smoking.

Methods:

Participants were a subsample of 1,900 unrelated individuals with genotype data drawn from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. Linear regression was used to examine relationships among self-reported ADHD symptoms, genotype, and self-reported initial reactions to cigarettes (index scores reflecting pleasant and unpleasant reactions).

Results:

Polymorphisms in the DRD2 gene, SLC6A4 gene, and among males, the MAOA gene interacted with retrospective reports of ADHD symptoms in predicting pleasant initial reaction to cigarettes. Polymorphisms in the CYP2A6 gene and, among females, the MAOA gene interacted with retrospective reports of ADHD symptoms in predicting unpleasant initial reaction to cigarettes. No main effect for any of these polymorphisms was observed nor were any interactions with DRD4 and DAT genes.

Conclusions:

These findings suggest that genotypes associated with monoamine neurotransmission interact with ADHD symptoms to influence initial reactions to cigarette smoking. Given that an initial pleasant reaction to cigarettes increases risk for lifetime smoking, these results add to a growing body of literature that suggests that ADHD symptoms increase risk for smoking and should be accounted for in genetic studies of smoking.

Objective

Few studies have examined concordance between raters of ADHD symptoms in adults; there is less information on how well rating scales function in distinguishing adult ADHD from other disorders. This study examined these variables using the Conners Adult ADHD Rating Scales (CAARS).

Method

The sample included 349 adults evaluated for attention problems. Correlations and kappa values were calculated using self- and observer-ratings of item-level symptoms; sensitivity, specificity, and discriminant validity of cluster scores in predicting clinician diagnoses were computed for 269 participants.

Results

Item-level concordance rates ranged from slight to fair. Cluster scores demonstrated a poor balance of sensitivity and specificity in predicting ADHD diagnosis; a high percentage of participants with internalizing disorders had scores in the clinical range.

Conclusion

Self- and observer- ratings on the CAARS provide clinically relevant data about attention problems in adults, but the instrument does not effectively distinguish between ADHD and other adult psychiatric disorders.

Introduction:

Smokers with attention deficit hyperactivity disorder (ADHD) have greater difficulty quitting than those without ADHD, but preliminary data (McClernon, Kollins, Lutz, Fitzgerald, Murray, Redman, et al., 2008) suggest equivalent severity of withdrawal symptoms following brief abstinence. The objective of this study was to characterize the differential effects of intermediate term smoking abstinence on self-reported withdrawal and ADHD symptoms in adult smokers with and without ADHD.

Methods:

Forty adult (50% female), nontreatment seeking moderate-to-heavy smokers with and without ADHD were enrolled in a 12-day quit study in which monetary incentives were provided for maintaining biologically verified abstinence. Self-reported withdrawal, mood, and ADHD symptoms were measured pre- and post-quitting.

Results:

ADHD and controls did not vary on smoking or demographic variables. Significant Group × Session interactions were observed across a broad range of withdrawal symptoms and were generally characterized by greater withdrawal severity among ADHD smokers, particularly during the first 5 days of abstinence. In addition, Group × Sex × Session interactions were observed for craving, somatic symptoms, negative affect, and habit withdrawal; these interactions were driven by greater withdrawal severity among females with ADHD. Group × Session interactions were not observed for ADHD symptom scales.

Conclusions:

The results of this study suggest that smokers with ADHD, and ADHD females in particular, experience greater withdrawal severity during early abstinence—independent of effects on ADHD symptoms. Whereas additional research is needed to pinpoint mechanisms, our findings suggest that smoking cessation interventions targeted at smokers with ADHD should address their more severe withdrawal symptoms following quitting.

Introduction:

This study investigated the association between retrospectively reported attention-deficit/hyperactivity disorder (ADHD) symptoms experienced during childhood and five cigarette smoking–related outcomes in adulthood.

Methods:

A large sample (N = 1,117) of new mothers participating in an ongoing longitudinal study completed retrospective reports of their childhood ADHD symptomatology, as well as concurrent and retrospective reports of their smoking behavior. Linear regression models tested the association between ADHD symptomatology and smoking outcomes.

Results:

Childhood ADHD symptomatology was predictive of the number of cigarettes smoked per day currently and during pregnancy, as well as the age at onset of smoking. We found nonlinear associations between hyperactive–impulsive symptoms and the number of cigarettes smoked per day in pregnancy, as well as between inattentive symptoms and the number of cigarettes smoked per day currently. Women who retrospectively reported intermediate levels of ADHD symptoms during their childhood reported smoking more cigarettes per day than women who reported low or high levels of ADHD symptoms during childhood. We also found multiplicative relationship between inattentive and hyperactive–impulsive symptoms, such that inattentive symptoms were predictive of an earlier age at smoking onset only when hyperactive–impulsive symptoms were low; moreover, the magnitude of this association was stronger for Black relative to White women.

Discussion:

These findings demonstrate the importance of considering differential effects of ADHD symptoms and smoking outcomes as a function of sex and race. They also represent a potentially indirect means through which women who have even a moderate childhood history of ADHD symptomatology may create a set of circumstances that compromise the health and well-being of their own children.

Objective

To examine associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort.

Design, Setting, and Participants

The study population consisted of 15,197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 – 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity, and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood.

Results

Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist-circumference, BMI, diastolic blood pressure, and systolic blood pressure (all ps for trend < .05). Controlling for demographic variables, physical activity, alcohol use, smoking, and depressive symptoms, those with 3 or more HI or IN symptoms had the highest odds of obesity (HI 3+ OR, 1.50; 95% CI, 1.22-2.83; IN 3+ OR, 1.21; 95% CI, 1.02-1.44) compared to those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+ OR, 1.24; 95% CI 1.01-1.51; HI continuous OR, 1.04; 95% CI 1.00-1.09), but associations were non-significant when models were adjusted for BMI. Latent growth modeling results indicated that compared to those reporting no HI or IN symptoms, those reporting more 3 or symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI.

Conclusion

Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.

Abstract

Background

Extended-release guanfacine (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6–17 years. This post-hoc analysis further examines the effects of GXR on hyperactivity-impulsivity and inattentiveness.

Method

Data from two large double-blind placebo-controlled pivotal trials of GXR in the treatment of ADHD were analyzed. Using the pooled population to provide sufficient sample size and associated statistical power, the impact of GXR treatment on core ADHD symptoms was examined by comparing ADHD Rating Scale IV (ADHD-RS-IV) total scores in the overall GXR and placebo groups in subjects with each of the three ADHD subtypes. ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores in the overall study population by randomized dose group (vs. placebo) were also examined.

Results

The full analysis set included 631 subjects aged 6–17 years (GXR: n=490; placebo: n=141). Among subjects with the predominantly inattentive subtype of ADHD, differences in least squares (LS) mean reductions from baseline in ADHD-RS-IV total scores were significantly greater in GXR-treated subjects (n=127) than in placebo-treated subjects (n=38) at treatment weeks 3 through 5 and end point (p≤0.020). Among subjects with combined type ADHD, differences in LS mean ADHD-RS-IV total score reductions from baseline were significantly greater in the GXR group (n=354) than in the placebo group (n=100) at treatment weeks 1 through 5 and end point (p≤0.011). The dearth of predominantly hyperactive-impulsive type subjects (n=12) precluded analysis of this subgroup. Each randomized GXR dose group in each trial demonstrated significantly greater reductions from baseline in ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores than did the respective placebo group at end point (p≤0.05 for all).

Conclusions

The results support the use of GXR in the treatment of core ADHD symptoms as defined in the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision, including hyperactivity, impulsivity, and inattention.

OBJECTIVE:

To assess the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) combined with stimulants (ie, methylphenidate or amphetamine) for attention-deficit/hyperactivity disorder (ADHD).

PATIENTS AND METHODS:

In this phase 3, double-blind, placebo-controlled trial, children and adolescents with hyperactive- or combined-subtype ADHD who had an inadequate response to their stable stimulant regimen were randomized to receive CLON-XR or placebo in combination with their baseline stimulant medication. Predefined efficacy measures evaluated change from baseline to week 5. Safety was assessed by spontaneously reported adverse events, vital signs, electrocardiogram recordings, and clinical laboratory values. Improvement from baseline for all efficacy measures was evaluated using analysis of covariance.

RESULTS:

Of 198 patients randomized, 102 received CLON-XR plus stimulant and 96 received placebo plus stimulant. At week 5, greater improvement from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (95% confidence interval: −7.83 to −1.13; P = .009), ADHD-RS-IV hyperactivity and inattention subscale scores (P = .014 and P = .017, respectively), Conners' Parent Rating Scale scores (P < .062), Clinical Global Impression of Severity (P = .021), Clinical Global Impression of Improvement (P = .006), and Parent Global Assessment (P = .001) was observed in the CLON-XR plus stimulant group versus the placebo plus stimulant group. Adverse events and changes in vital signs in the CLON-XR group were generally mild.

CONCLUSIONS:

The results of this study suggest that CLON-XR in combination with stimulants is useful in reducing ADHD in children and adolescents with partial response to stimulants.

Objective

This study investigated the role of self-regulation of emotion in relation to functional impairment and comorbidity among children with and without AD/HD.

Method

A total of 358 probands and their siblings participated in the study, with 74% of the sample participants affected by AD/HD. Parent-rated levels of emotional lability served as a marker for self-regulation of emotion.

Results

Nearly half of the children affected by AD/HD displayed significantly elevated levels of emotional lability versus 15% of those without this disorder. Children with AD/HD also displayed significantly higher rates of functional impairment, comorbidity, and treatment service utilization. Emotional lability partially mediated the association between AD/HD status and these outcomes.

Conclusion

Findings lent support to the notion that deficits in the self-regulation of emotion are evident in a substantial number of children with AD/HD and that these deficits play an important role in determining functional impairment and comorbidity outcomes.

Objective

To explore dose–response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD.

Method

This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) criteria for ADHD.

Results

Nearly all participants assigned to an LDX dose achieved their assigned dose with the exception of about 4% of participants assigned to the 50 mg or 14% assigned to the 70 mg doses. Higher doses of LDX led to greater improvements in ADHD-rating scale scores, independent of prior pharmacotherapy. This was evident for both inattentive and hyperactive–impulsive symptoms. The authors found some evidence for an interaction between LDX dose and baseline severity of ADHD symptoms.

Conclusion

For LDX doses between 30 and 70 mg/d, the dose–response efficacy effect for LDX is not affected by prior pharmacotherapy, but patients with a greater severity of illness may benefit more from higher doses, especially for hyperactive–impulsive symptoms. The results do not provide information about doses above 70 mg/d, which is the maximum approved dose of LDX and the highest dose studied in ADHD clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder, and the phenotypic structure comprising inattentive and hyperactive-impulsive type symptoms has been the focus of a growing body of recent research. Methodological studies are needed to better characterize phenotypes to advance research as well as clinical practice. A large U.S. population-based sample of young adults (N = 14,307, aged 17–28 years, 52.8% female) retrospectively reported their experiences of childhood ADHD symptoms. Factor analysis, latent class analysis, and factor mixture modeling of ADHD symptoms were compared to determine which underlying structure best fit the data. Fit statistics as well as substantive criteria compared models within and across model subtypes. Analyses supported a two-factor two-class structure for both male and female subjects. The two latent factors represented inattentive and hyperactive-impulsive symptom dimensions. The two latent classes divided people into a smaller affected class and a larger unaffected class. Individuals who reported having been diagnosed with ADHD were more likely to be in the affected class (OR male subjects = 4.03, 95% CI [2.65, 6.13]; OR female subjects = 5.65, 95% CI [3.15, 10.10]). This work aids in the understanding of ADHD symptomatology within the population; a majority of people experience very low symptom severity, whereas a minority of people experience high symptom severity. Within this high symptom group, however, variability in symptom experiences exists. Empirical models can be helpful in clarifying ADHD phenotypic structure that has the potential to advance research on the etiology and consequences of ADHD symptoms.

Attention-deficit hyperactivity disorder (ADHD) is associated with multiple cognition-related phenotypic features in both children and adults. This review aims to clarify the role of cognition in ADHD and how prevailing treatments, which are often highly effective at reducing the clinical symptoms of the disorder, fare in modulating ADHD-related cognitive processes. First, we consider how the broad construct of cognition can be conceptualized in the context of ADHD. Second, we review the available evidence for how a range of both pharmacological and non-pharmacological interventions have fared with respect to enhancing cognition in individuals affected by this pervasive disorder. Findings from the literature suggest that the effects across a broad range of pharmacological and non-pharmacological interventions on the characteristic symptoms of ADHD can be distinguished from their effects on cognitive impairments. As such the direct clinical relevance of cognition enhancing effects of different interventions is somewhat limited. Recommendations for future research are discussed, including the identification of cognition-related end ophenotypes, the refinement of the ADHD clinical phenotype, and studying the difference between acute and chronic treatment regimens.

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D2/D3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

ADHD is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using PET we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which we hypothesized could underlie the motivation deficits in this disorder. To evaluate this hypothesis we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [11C]raclopride and [11C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens), and a surrogate measures of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, p<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, p<0.008; midbrain: r=0.41, p<0.005) and transporters (accumbens: r=0.35, p < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN-I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

OBJECTIVE:

To evaluate the efficacy and tolerability of atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children.

METHODS:

This was an 8-week, double-blind, placebo-controlled randomized clinical trial of atomoxetine in 101 children with ADHD. Atomoxetine or placebo was flexibly titrated to a maximum dose of 1.8 mg/kg per day. The pharmacotherapist reviewed psychoeducational material on ADHD and behavioral-management strategies with parents during each study visit.

RESULTS:

Significant mean decreases in parent (P = .009) and teacher (P = .02) ADHD–IV Rating Scale scores were demonstrated with atomoxetine compared with placebo. A total of 40% of children treated with atomoxetine met response criteria (Clinical Global Impression–Improvement Scale indicating much or very much improved) compared with 22% of children on placebo, which was not significant (P = .1). Decreased appetite, gastrointestinal upset, and sedation were significantly more common with atomoxetine than placebo. Although some children demonstrated a robust response to atomoxetine, for others the response was more attenuated. Sixty-two percent of subjects who received atomoxetine were moderately, markedly, or severely ill according to the Clinical Global Impression–Severity Scale at study completion.

CONCLUSIONS:

To our knowledge, this is the first randomized controlled trial of atomoxetine in children as young as 5 years. Atomoxetine generally was well tolerated and reduced core ADHD symptoms in the children on the basis of parent and teacher reports. Reductions in the ADHD-IV Rating Scale scores, however, did not necessarily translate to overall clinical and functional improvement, as demonstrated on the Clinical Global Impression–Severity Scale and the Clinical Global Impression–Improvement Scale. Despite benefits, the children in the atomoxetine group remained, on average, significantly impaired at the end of the study.

Smokers exhibit decrements in inhibitory control (IC) during withdrawal. The objective of this study was to investigate the neural basis of these effects in critical substrates of IC—right inferior frontal cortex (rIFC) and presupplementary motor area (pre-SMA). Smokers were scanned following smoking as usual and after 24-h smoking abstinence. During scanning they completed a Go/No-Go task that required inhibiting responses to infrequent STOP trials. Event-related brain activation in response to successfully inhibited STOP trials was evaluated in two regions of interest: rIFC (10 mm sphere, x=40, y=30, z=26) and pre-SMA (10 mm sphere, x=2, y=18, z=40). Smoking abstinence robustly increased errors of commission on STOP trials (37.1 vs 24.8% in the satiated condition, p<0.001) while having no effects on GO trial accuracy or reaction time (RT). In rIFC, smoking abstinence was associated with a significantly increased event-related BOLD signal (p=0.026). Pre-SMA was unaffected by smoking condition. The results of this preliminary study suggest that successful IC during withdrawal is associated with increased processing demands on a cortical center associated with attention to inhibitory signals.

Smokers exhibit decrements in inhibitory control (IC) during withdrawal. The objective of the current study was to investigate the neural basis of these effects in critical substrates of IC—right inferior frontal cortex (rIFC) and pre-supplementary motor area (pre-SMA). Smokers were scanned following smoking as usual and after 24-hrs smoking abstinence. During scanning they completed a Go/No-Go task which required inhibiting responses to infrequent STOP trials. Event-related brain activation in response to successfully inhibited STOP trials was evaluated in two regions of interest: rIFC (10 mm sphere, x=40, y=30, z=26) and pre-SMA (10 mm sphere, x=2, y=18, z=40). Smoking abstinence robustly increased errors of commission on STOP trials (37.1% versus 24.8% in satiated condition, p<.001) while having no effects on GO trial accuracy or reaction time (RT). In rIFC, smoking abstinence was associated with significantly increased event-related BOLD signal (p=.026). Pre-SMA was unaffected by smoking condition. The results of this preliminary study suggest that successful IC during withdrawal is associated with increased processing demands on a cortical center associated with attention to inhibitory signals.

Objective

A family was previously identified that cosegregates a pericentric inversion, inv(3)(p14 : q21), with an early-onset developmental condition, characterized by impulsive behavior and intellectual deficit. The inversion breakpoints lie within DOCK3 and SLC9A9 at the p-arm and q-arm, respectively. Based on this report, these genes were selected to be evaluated in a family-based attention-deficit/hyperactivity disorder (AD/HD) association study.

Methods

Conners’ Parent (CPRS) and Teacher (CTRS) Rating Scales of AD/HD symptoms and Conners’ Continuous Performance Test (CPT) measures were collected and a minimal number of tagging singlenucleotide polymorphisms (SNPs) in each gene were selected for analysis. Analyses were performed on families who met research criteria for AD/HD. Using the program, QTDT, each tagging SNP was tested for association with T-scores from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) subscales according to the CTRS and CPRS, and five CPT measures.

Results

After adjusting for multiple testing, a SNP in the 3′ UTR of SLC9A9, rs1046706, remained significantly associated (false discovery rate, q value < 0.05) with scores on the DSM-IV hyperactive-impulsive and total symptom subscales according to the CTRS and errors of commission on the CPT. In addition, an intronic SLC9A9 SNP, rs2360867, remained significantly associated with errors of commission.

Conclusion

Our results suggest that SLC9A9 may be related to hyperactive-impulsive symptoms in AD/HD and the disruption of SLC9A9 may be responsible for the behavioral phenotype observed in the inversion family. The association with SLC9A9 is particularly interesting as it was recently implicated in a genome-wide association study for AD/HD. Further investigation of the role of SLC9A9 in AD/HD and other behavioral disorders is warranted.

Background

Efficacy and safety profiles by sex and age (6-9 vs 10-12 years) and magnitude and duration of effect by effect size overall and across the day of lisdexamfetamine dimesylate (LDX) vs placebo were assessed.

Methods

This study enrolled children (6-12 years) with attention-deficit/hyperactivity disorder (ADHD) in an open-label dose optimization with LDX (30-70 mg/d) followed by a randomized, double-blind, placebo-controlled, 2-way crossover phase. Post hoc analyses assessed interaction between sex or age and treatment and assessed effect sizes for Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and Permanent Product Measure of Performance (PERMP) scales and ADHD Rating Scale IV measures. No corrections for multiple testing were applied on time points and subgroup statistical comparisons.

Results

129 participants enrolled; 117 randomized. Both sexes showed improvement on all assessments at postdose time points; females showed less impairment than males for SKAMP and PERMP scores in treatment and placebo groups at nearly all times. Both age groups improved on all assessments at postdose time points. Children 10-12 years had less impairment in SKAMP ratings than those 6-9 years. Treatment-by-sex interactions were observed at time points for SKAMP-D, SKAMP total, and PERMP scores; no consistent pattern across scales or time points was observed. LDX demonstrated significant improvement vs placebo, by effect size, on SKAMP-D from 1.5-13 hours postdose. The overall LS mean (SE) SKAMP-D effect size was -1.73 (0.18). In the dose-optimization phase, common (≥2%) treatment-emergent adverse events (TEAEs) in males were upper abdominal pain, headache, affect lability, initial insomnia, and insomnia; in females were nausea and decreased weight. During the crossover phase for those taking LDX, higher incidence (≥2% greater) was observed in males for upper abdominal pain and insomnia and in females for nausea and headache. Overall incidence of TEAEs in age groups was similar.

Conclusion

Apparent differences in impairment level between sex and age groups were noted. However, these results support the efficacy of LDX from 1.5 hours to 13 hours postdose in boys and girls with medium to large effect sizes across the day with some variability in TEAE incidence by sex.

Trial Registration Number

ClinicalTrials.gov Identifier: NCT00500149.

Context

Attention-deficit/hyperactivity disorder (ADHD)—characterized by symptoms of inattention and hyperactivity-impulsivity—is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder.

Objective

To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens).

Design, Setting, and Participants

We used positron emission tomography to measure dopamine synaptic markers (transporters and D2/D3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001–2009 at Brookhaven National Laboratory.

Main Outcome Measures

We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [11C]cocaine and for D2/D3 receptors using [11C]raclopride, quantified as binding potential (distribution volume ratio −1).

Results

For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P<.005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03–0.13, P=.004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03–0.12; P ≤ .001); for D2/D3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06–0.30, P=.004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02–0.17, P=.01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04–0.22; P=.003) and the mean D2/D3 for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10–0.56; P=.005) and differences in D2/D3 in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02–0.12; P=.004). Ratings of attention correlated with D2/D3 in the accumbens (r =0.35; 95% CI, 0.15–0.52; P =.001), midbrain (r=0.35; 95% CI, 0.14–0.52; P=.001), caudate (r=0.32; 95% CI, 0.11–0.50; P=.003), and hypothalamic (r=0.31; CI, 0.10–0.49; P=.003) regions and with DAT in the midbrain (r=0.37; 95% CI, 0.16–0.53; P ≤ .001).

Conclusion

A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.

Objective

This study addressed the hypothesis that variation in genes associated with dopamine function (SLC6A3, DRD2, DRD4), serotonin function (SLC6A4), and regulation of monoamine levels (MAOA) may be predictive of BMI categories (obese and overweight + obese) in young adulthood and of changes in BMI as adolescents transition into young adulthood. Interactions with gender and race/ethnicity were also examined.

Research Methods and Procedures

Participants were a subsample of individuals from The National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset of 1584 unrelated individuals with genotype data. Multiple logistic regressions were conducted to evaluate associations between genotypes and obesity (BMI > 29.9) or overweight + obese combined (BMI > 25) with normal weight (BMI = 18.5–24.9) as a referent. Linear regression models were used examine change in BMI from adolescence to young adulthood.

Results

Significant associations were found between SLC6A4 5HTTLPR and categories of BMI, and between MAOA promoter VNTR among males and categories of BMI. Stratified analyses revealed that the association between these two genes and excess BMI was significant for males overall, and for White and Hispanic males specifically. Linear regression models indicated a significant effect of SLC6A4 5HTTLPR on change in BMI from adolescence to young adulthood.

Discussion

Our findings lend further support to the involvement of genes implicated in dopamine and serotonin regulation on energy balance.

Background

Depression and Genetic variation in serotonin and monoamine transmission have both been associated with Body Mass Index (BMI), but their interaction effects are not well understood. We examined the interaction between depressive symptoms and functional polymorphisms of serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) on categories of BMI.

Methods

Participants were from the National Longitudinal Study of Adolescent Health. Multiple logistic regression was used to investigate interactions between candidate genes and depression on risk of obesity (BMI≥30) or overweight + obese combined (BMI≥25).

Results

Males with an MAOA active allele with high depressive symptoms were at decreased risk of obesity (OR, 0.22; 95% CI, 0.06 – 0.78) and overweight + obesity (OR, 0.48; 95% CI, 0.26 – 0.89). No similar effect was observed among females.

Conclusions

These findings highlight that the obesity-depression relationship may vary as a function of gender and genetic polymorphism, and suggest the need for further study.

Smoking abstinence differentially affects cognitive functioning in smokers with ADHD, compared to non-ADHD smokers. Alternative approaches for analyzing reaction time data from these tasks may further elucidate important group differences. Adults smoking ≥15 cigarettes with (n = 12) or without (n = 14) a diagnosis of ADHD completed a continuous performance task (CPT) during two sessions under two separate laboratory conditions—a ‘Satiated’ condition wherein participants smoked up to and during the session; and an ‘Abstinent’ condition, in which participants were abstinent overnight and during the session. Reaction time (RT) distributions from the CPT were modeled to fit an ex-Gaussian distribution. The indicator of central tendency for RT from the normal component of the RT distribution (mu) showed a main effect of Group (ADHD Satiated), Group × Session interaction (ADHD increased significantly under Abstinent condition compared to Control), and a trend toward a main effect of Group (ADHD > Control). Alternative approaches to analyzing RT data provide a more detailed description of the effects of smoking abstinence in ADHD and non-ADHD smokers and results differ from analyses using more traditional approaches. These findings have implications for understanding the neuropsychopharmacology of nicotine and nicotine withdrawal.

Background

Lisdexamfetamine dimesylate (LDX) is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6 to 12 years of age and in adults. In a previous laboratory school study, LDX demonstrated efficacy 2 hours postdose with duration of efficacy through 12 hours. The current study further characterizes the time course of effect of LDX.

Methods

Children aged 6 to 12 years with ADHD were enrolled in a laboratory school study. The multicenter study consisted of open-label, dose-optimization of LDX (30, 50, 70 mg/d, 4 weeks) followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each). Efficacy measures included the SKAMP (deportment [primary] and attention [secondary]) and PERMP (attempted/correct) scales (secondary) measured at predose and at 1.5, 2.5, 5, 7.5, 10, 12, and 13 hours postdose. Safety measures included treatment-emergent adverse events (AEs), physical examination, vital signs, and ECGs.

Results

A total of 117 subjects were randomized and 111 completed the study. Compared with placebo, LDX demonstrated significantly greater efficacy at each postdose time point (1.5 hours to 13.0 hours), as measured by SKAMP deportment and attention scales and PERMP (P < .005). The most common treatment-emergent AEs during dose optimization were decreased appetite (47%), insomnia (27%), headache (17%), irritability (16%), upper abdominal pain (16%), and affect lability (10%), which were less frequent in the crossover phase (6%, 4%, 5%, 1%, 2%, and 0% respectively).

Conclusion

In school-aged children (6 to 12 years) with ADHD, efficacy of LDX was maintained from the first time point (1.5 hours) up to the last time point assessed (13.0 hours). LDX was generally well tolerated, resulting in typical stimulant AEs.

Trial registration

Official Title: A Phase IIIb, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Dose-Optimization, Cross-Over, Analog Classroom Study to Assess the Time of Onset of Vyvanse (Lisdexamfetamine Dimesylate) in Pediatric Subjects Aged 6–12 With Attention-Deficit/Hyperactivity Disorder.

ClinicalTrials.gov Identifier: NCT00500149

Rationale

There has been controversy over the abuse potential of methylphenidate (MPH) in the context of treatment for attention deficit hyperactivity disorder (ADHD).

Objective

The objective of this study was to compare the reinforcing and subjective effects of oral MPH in adults with and without ADHD.

Materials and methods

Following screening, 33 adults (n= 16 with ADHD; n=17 free from psychiatric diagnoses) completed four pairs of experimental sessions, each of which included a sampling session and a self-administration session. During sampling sessions, subjects received in randomized order 0 (placebo), 20, 40, and 60 mg MPH. During self-administration sessions, subjects completed a progressive ratio (PR) task to earn portions of the dose received on the corresponding sampling session. Subjective effects were recorded throughout all sessions. The main outcome measure for the study was the number of ratios completed on the PR task. Secondary measures included peak subjective effects and area-under-the-curve values for subjective effects.

Results

Compared to the control group, the ADHD group completed more ratios on the PR task. Both groups showed robust effects of methylphenidate on subjective endpoints. Main effects of group were noted on subjective effects involving concentration and arousal.

Conclusions

Compared to placebo, MPH produced reinforcing effects only for the ADHD group and not for the control group. Increases in stimulant-related subjective effects in non-ADHD subjects were not associated with drug reinforcement.