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1.  A Pilot Study of Lis-Dexamfetamine Dimesylate (LDX/SPD489) to Facilitate Smoking Cessation in Nicotine-Dependent Adults With ADHD 
Journal of attention disorders  2012;18(2):10.1177/1087054712440320.
The goal of this study was to assess the efficacy and tolerability of lis-dexamfetamine dimesylate (LDX) as an adjunct to nicotine replacement therapy in adult smokers with ADHD who were undergoing a quit attempt.
Thirty-two regular adult smokers with ADHD were randomized to receive LDX (n = 17) or placebo (n = 15) in addition to nicotine patch concurrent with a quit attempt.
There were no differences between smokers assigned to LDX versus placebo in any smoking outcomes. Participants treated with LDX demonstrated significant reductions in self-reported and clinician-rated ADHD symptoms. LDX was well tolerated in smokers attempting to quit.
In general, LDX does not facilitate smoking cessation in adults with ADHD more than does placebo, though both groups significantly reduced smoking. LDX demonstrated efficacy for reducing ADHD symptoms in adult smokers engaging in a quit attempt.
PMCID: PMC3421044  PMID: 22508760
adult ADHD; lis-dexamfetamine dimesylate; smoking
2.  Alpha-2 Adrenergic Receptors and Attention—Deficit/Hyperactivity Disorder 
Current psychiatry reports  2010;12(5):366-373.
Pharmacological management of attention-deficit hyperactivity disorder (ADHD) has expanded beyond stimulant medications to include alpha 2 adrenergic agonists. These agents exert their actions through presynaptic stimulation and likely involve facilitation of both dopamine and noradrenaline neurotransmission, which are both thought to play critical roles in the pathophysiology of ADHD. Further, frontostratial dysfunction giving rise to neuropsychological weaknesses has been well-established in patients with ADHD and may explain how alpha 2 agents exert their beneficial effects. In the following review, we consider relevant neurobiological underpinnings of ADHD with respect to why alpha 2 agents may be effective in treating this condition. We also review new formulations of alpha 2 agonists, emerging data on their use in ADHD, and implications for clinical practice. Integrating knowledge of pathphysiological mechanisms and mechanisms of drug action may inform our medication choices and facilitate treatment of ADHD and related disorders.
PMCID: PMC3676929  PMID: 20652773
guanfacine; clonidine; prefrontal; noradrenaline; ADHD
3.  Analysis of individual items on the attention-deficit/hyperactivity disorder symptom rating scale in children and adults: the effects of age and sex in pivotal trials of lisdexamfetamine dimesylate 
Attention-deficit/hyperactivity disorder (ADHD) symptom presentation across age and sex has not been fully elucidated. The present post hoc analyses qualitatively explored the baseline levels of ADHD symptomatology across subgroups in two clinical trials of children and adults with ADHD to elucidate differences in participant presentation. The response to treatment was examined to determine patterns of response among items of the ADHD Rating Scale IV.
Exploratory post hoc analyses of ADHD Rating Scale IV item scores were conducted on data from two 4-week placebo-controlled trials in children (6–12 years) and in adults (18–55 years) with ADHD. Baseline and endpoint mean item scores were determined for subgroups defined by age (6–9, 10–12, 18–39, and 40–55 years) and sex.
The baseline mean item scores were generally numerically similar for all age-by-sex subgroups. The inattention (IA) items were numerically higher than hyperactivity/impulsivity (H/I) items among older children and adults. The endpoint mean item scores were numerically lower after lisdexamfetamine dimesylate treatment for IA and H/I items in all subgroups.
These results suggest that regardless of age or sex, baseline IA and H/I symptom profiles were comparable; however, IA vs H/I symptoms were more severe in older participants. In all age-by-sex subgroups, IA and H/I symptoms appeared to decrease after active treatment.
PMCID: PMC3862743  PMID: 24363557
ADHD symptom items
4.  Monetary Incentives Promote Smoking Abstinence in Adults With Attention Deficit Hyperactivity Disorder (ADHD) 
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.
PMCID: PMC3354633  PMID: 20545386
ADHD; smoking; nicotine dependence; contingency management
5.  Assessing the Role of Attention-Deficit/Hyperactivity Disorder Symptoms in Smokers With and Without Posttraumatic Stress Disorder 
Nicotine & Tobacco Research  2011;14(8):986-992.
Smoking prevalence among individuals with posttraumatic stress disorder (PTSD) is elevated relative to non–PTSD smokers, and there is evidence to suggest that affect regulation may be a motivation for smoking among those with this disorder. Previous studies have also indicated that (a) PTSD is frequently comorbid with attention-deficit/hyperactivity disorder (ADHD), (b) individuals with ADHD smoke at significantly higher rates than the general population, (c) subclinical ADHD symptoms are a risk factor for smoking, and (d) affect regulation is a motivation for smoking in ADHD. The goal of this study was to assess the degree to which ADHD symptoms were uniquely associated with smoking-related affective functioning (SRAF) variables above and beyond the variance already explained by PTSD symptoms.
Smokers with (n = 55) and without PTSD (n = 68) completed measures assessing PTSD symptoms, ADHD symptoms, and SRAF.
The PTSD group endorsed significantly more severe levels of DSM-IV inattentive and hyperactive–impulsive ADHD symptoms. A series of hierarchical regressions among the entire sample indicated that, after accounting for PTSD symptoms, ADHD symptoms were associated with lower positive affect, higher negative affect, higher emotion dysregulation, higher anxiety sensitivity, and higher urges to smoke to increase positive affect.
Taken together, these findings suggest that ADHD symptoms may increase affective dysregulation difficulties already faced by smokers, particularly those with PTSD, which may, in turn, confer increased risk for smoking relapse in those with higher levels of symptomatology of both disorders.
PMCID: PMC3439866  PMID: 22180583
6.  Treatment for Co-Occurring Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder 
Neurotherapeutics  2012;9(3):518-530.
Interest in the co-occurrence of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) has grown in the last decade. Research on clinical populations supports the frequent co-occurrence of ADHD traits (e.g., hyperactivity) in individuals with ASD and ASD traits (e.g., social communication deficits) in individuals with ADHD. Similar trends in co-occurring traits have been observed in population-based samples, as well as family and genetic studies of affected individuals. Despite increased interest in co-occurring ADHD and ASD, relatively little research has been devoted to treatment considerations. The vast majority of intervention research has examined pharmacological treatment using traditional ADHD medications. Relatively few psychosocial interventions have directly addressed co-occurring symptoms. Treatment development will benefit from enhanced understanding of the phenomenon of co-occurring ADHD and ASD. Key topics for future research include examining developmental trajectories of co-occurring disorders, comorbid psychiatric conditions, deficits in social skills, and the nature of executive functioning impairment in individuals with co-occurring ADHD and ASD. In the current review, research in these areas is reviewed along with recommendation for future study. Given that clinicians are routinely observing and treating individuals with co-occurring symptoms, further research will yield needed information to inform intervention development and maximize benefits for affected individuals.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0126-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3441928  PMID: 22678458
ADHD; autism spectrum disorder; psychopharmacology; psychosocial treatment
7.  Effects of Postnatal Parental Smoking on Parent and Teacher Ratings of ADHD and Oppositional Symptoms 
To assess the effects of postnatal parental smoking on subsequent parent and teacher ratings of DSM-IV attention deficit hyperactivity disorder (ADHD) symptoms and oppositional behaviors in children diagnosed with ADHD and their siblings. Children between 5 and 12 years of age with ADHD and their siblings were included. DSM-IV ADHD symptom subscales (Inattentive and hyperactive-impulsive), and oppositionality subscale scores from Conners’ Rating Scales were predicted on the basis of parental smoking status in the first 7 years after birth using Generalized Estimating Equations controlling for a range of relevant covariates. Postnatal parental smoking was associated with both parent and teacher ratings of ADHD symptoms and oppositional behavior. After controlling for a number of covariates, several of these relationships were still significant. The risk of maternal smoking for the development of ADHD symptoms does not end during pregnancy. Research on the mechanisms underlying the observed associations is needed.
PMCID: PMC3678953  PMID: 19525745
ADHD; smoking; disruptive behavior; nicotine dependence
8.  Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder 
PLoS ONE  2013;8(5):e63023.
Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.
We used positron emission tomography and [11C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands.
Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005).
Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.
PMCID: PMC3655054  PMID: 23696790
9.  Sex, ADHD symptoms, and smoking outcomes: An integrative model 
Medical Hypotheses  2012;78(5):585-593.
Both females and individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) have been found to be at increased risk for a range of smoking outcomes, and recent empirical findings have suggested that women with ADHD may be particularly vulnerable to nicotine dependence. On a neurobiological level, the dopamine reward processing system may be implicated in the potentially unique interaction of nicotine with sex and with ADHD status. Specifically, nicotine appears to mitigate core ADHD symptoms through interaction with the dopamine reward processing system, and ovarian hormones have been found to interact with nicotine within the dopamine reward processing system to affect neurotransmitter release and functioning.
This article synthesizes data from research examining smoking in women and in individuals with ADHD to build an integrative model through which unique risk for cigarette smoking in women with ADHD can be systematically explored. Based upon this model, the following hypotheses are proposed at the intersection of each of the three variables of sex, ADHD, and smoking: 1) Individuals with ADHD have altered functioning of the dopamine reward system, which diminishes their ability to efficiently form conditioned associations based on environmental contingencies; these deficits are partially ameliorated by nicotine; 2) Nicotine interacts with estrogen and the dopamine reward system to increase the positive and negative reinforcement value of smoking in female smokers; 3) In adult females with ADHD, ovarian hormones interact with the dopamine reward system to exacerbate ADHD-related deficits in the capacity to form conditioned associations; and 4) During different phases of the menstrual cycle, nicotine and ovarian hormones may interact differentially with the dopamine reward processing system to affect the type and value of reinforcement smoking provides for women with ADHD.
Understanding the bio-behavioral mechanisms underlying cigarette addiction in specific populations will be critical to developing effectively tailored smoking prevention and cessation programs for these groups. Overall, the goal of this paper is to examine the interaction of sex, smoking, and ADHD status within the context of the dopamine reward processing system not only to elucidate potential mechanisms specific to female smokers with ADHD, but also to stimulate consideration of how the examination of such individual differences can inform our understanding of smoking more broadly.
PMCID: PMC3321070  PMID: 22341778
10.  Association between smoking and retrospectively reported attention-deficit/hyperactivity disorder symptoms in a large sample of new mothers 
Nicotine & Tobacco Research  2009;11(3):313-322.
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.
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.
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.
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.
PMCID: PMC2666380  PMID: 19307443
11.  A Preliminary Analysis of Interactions Between Genotype, Retrospective ADHD Symptoms, and Initial Reactions to Smoking in a Sample of Young Adults 
Nicotine & Tobacco Research  2011;14(2):229-233.
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.
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).
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.
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.
PMCID: PMC3265740  PMID: 21778150
12.  Reliability and Validity of Self- and Other-Ratings of Symptoms of ADHD in Adults 
Journal of attention disorders  2010;15(3):224-234.
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).
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.
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.
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.
PMCID: PMC3556723  PMID: 20424007
Adult ADHD; reliability; rating scales; sensitivity; specificity
13.  Smoking Withdrawal Symptoms Are More Severe Among Smokers With ADHD and Independent of ADHD Symptom Change: Results From a 12-Day Contingency-Managed Abstinence Trial 
Nicotine & Tobacco Research  2011;13(9):784-792.
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.
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.
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.
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.
PMCID: PMC3203401  PMID: 21571687
14.  Association between Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms and obesity and hypertension in early adulthood: A population-based study 
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.
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.
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.
PMCID: PMC3391591  PMID: 20975727
attention-deficit/hyperactivity disorder; obesity; hypertension; young adult; risk factors
15.  Efficacy of Guanfacine Extended Release in the Treatment of Combined and Inattentive Only Subtypes of Attention-Deficit/Hyperactivity Disorder 
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.
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.
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).
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.
PMCID: PMC3373219  PMID: 22612526
16.  Clonidine Extended-Release Tablets as Add-on Therapy to Psychostimulants in Children and Adolescents With ADHD 
Pediatrics  2011;127(6):e1406-e1413.
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).
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.
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.
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.
PMCID: PMC3387872  PMID: 21555501
α2-adrenergic agonist; attention-deficit/hyperactivity disorder; clonidine–hydrochloride extended-release tablets; psychostimulant
17.  Self-Regulation of Emotion, Functional Impairment, and Comorbidity Among Children With AD/HD 
Journal of Attention Disorders  2010;15(7):583-592.
This study investigated the role of self-regulation of emotion in relation to functional impairment and comorbidity among children with and without AD/HD.
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.
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.
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.
PMCID: PMC3355528  PMID: 20686097
AD/HD; children; emotion regulation; comorbidity; functional impairment
18.  Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults With ADHD: An Exploratory Study 
Journal of Attention Disorders  2011;16(2):118-127.
To explore dose–response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD.
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.
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.
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.
PMCID: PMC3355536  PMID: 21527575
ADHD; dose–response; lisdexamfetamine dimesylate; amphetamine; stimulants
19.  Understanding the Phenotypic Structure of Adult Retrospective ADHD Symptoms During Childhood in the United States 
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.
PMCID: PMC3354630  PMID: 22394329
20.  Cognitive enhancers for the treatment of ADHD 
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.
PMCID: PMC3353150  PMID: 21596055
ADHD; Cognition; Pharmacological treatment
21.  Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder 
The Journal of Neuroscience  2012;32(3):841-849.
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.
PMCID: PMC3350870  PMID: 22262882
22.  Motivation Deficit in ADHD is Associated with Dysfunction of the Dopamine Reward Pathway 
Molecular psychiatry  2010;16(11):1147-1154.
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.
PMCID: PMC3010326  PMID: 20856250
psychiatric disorder; brain imaging; PET; attention; catecholamines; personality
23.  A Double-Blind, Placebo-Controlled Study of Atomoxetine in Young Children With ADHD 
Pediatrics  2011;127(4):e862-e868.
To evaluate the efficacy and tolerability of atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children.
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.
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.
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.
PMCID: PMC3387889  PMID: 21422081
ADHD; atomoxetine; child; pharmacotherapy
24.  Smoking Withdrawal Modulates Right Inferior Frontal Cortex but not Presupplementary Motor Area Activation During Inhibitory Control 
Neuropsychopharmacology  2010;35(13):2600-2606.
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.
PMCID: PMC2978758  PMID: 20861830
inhibitory control; smoking; fMRI; withdrawal; inferior frontal cortex; pre-supplementary motor area; Addiction & Substance Abuse; Psychiatry & Behavioral Sciences; Cognition; Psychopharmacology; inhibitory control; smoking, fMRI; withdrawal; inferior frontal cortex; presupplementary motor area
25.  Smoking withdrawal modulates right inferior frontal cortex but not pre-supplementary motor area activation during inhibitory control 
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.
PMCID: PMC2978758  PMID: 20861830
inhibitory control; smoking; fMRI; withdrawal; inferior frontal cortex; presupplementary motor area

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