From MedscapeCME Psychiatry & Mental Health

Pediatric ADHD Highlights From APA 2010 CME

Craig B.H. Surman, MD; Jennifer M. Covino, MPA

Posted: 07/15/2010

New research presented at the 2010 meeting of the American Psychiatric Association in New Orleans, Louisiana, included a Turkish study discussing the international prevalence of attention-deficit/hyperactivity disorder (ADHD), data on stimulant use and safety, and clinical challenges pertaining to adherence and comorbidity in the treatment of ADHD.

International Prevalence of ADHD

Studies demonstrating the prevalence of ADHD in samples from different countries have fostered understanding of the worldwide importance of the condition. One meta-analytic review[1] that included data from 102 studies placed the worldwide prevalence of ADHD, defined by either DSM or ICD criteria, at 5.29%. This report concluded that the rate of ADHD is determined more by the diagnostic criteria applied than the country from which the population is from.

A study from Turkey[2] evaluated the prevalence of ADHD among 1500 randomly selected Turkish elementary school students who were originally screened in the second grade. The presence of ADHD was ascertained using the teacher and parent version of the DSM-IV-based ADHD scale, with at least 5 symptoms of inattention constituting a positive screen for inattentive subtype ADHD (ADHD-IA) and at least 5 symptoms of hyperactivity-impulsivity constituting a positive screen for the hyperactive-impulsive subtype (ADHD-HI). In all, 86 students screened positive, and the correlation of this screening measure was confirmed with the Kiddie-SADS structured interview.

Investigators estimated that the prevalence of ADHD was 13.4% in second-grade students (95% confidence interval [CI], 11.75-15.43); this percentage fell to 12.6% in the subsequent portion of the study, which was completed the following year, with the children in the third grade. Diagnosis of ADHD subtype revealed that the combined type was the most common subtype seen, at 44.6%, compared with 36.5% for ADHD-IA and 18.9% for ADHD-HI. These rates are somewhat higher than usual estimates of prevalence for ADHD. Of note, this study focused on a narrow age range and used a definition of ADHD that is subthreshold to the full 6 symptoms required by DSM-IV. Comparisons of rates of ADHD between countries would require direct matching of samples and methods, which has rarely been done in the literature.

Is Visual Memory an Endophenotype for ADHD?

An "endophenotype" is a measurable trait that lies on the pathway between genetics and a disease state, and thus provides clues to the genetics underlying the disease state. Chinese researchers presented data from a study exploring the possibility that visual memory is a potential endophenotype of ADHD.[3] The study enrolled 279 adolescents (ages 11-17) diagnosed with DSM-IV ADHD at age 6.7 2.9 years (re-assessed for current ADHD at 12.5 1.6 years), 108 unaffected siblings (older than 8 years of age at trial onset and currently 12.2 3.3 years), and 173 unaffected school controls. Exclusion criteria included subjects with psychosis, autism spectrum disorder, or a full scale IQ score < 80. Assessments included the Chinese version of the Kiddie epidemiologic version of the Schedule for Affective Disorders and Schizophrenia (K-SADS-E). Four subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) were also included.

Compared with their siblings and controls, subjects with ADHD had fewer correct responses in the Delayed Matching to Sample task. When compared with controls, the ADHD and unaffected siblings groups had a higher probability of an error following an error response. The researchers concluded that visual memory is impaired in children with ADHD and their unaffected siblings, indicating potential genetic determinants of these visual memory differences. Thus, visual memory may be an endophenotype for ADHD. This work adds to a small body of literature that has identified executive function, attention control, and response inhibition deficits in the unaffected siblings of children with ADHD.[4]

Pharmacotherapy of Pediatric ADHD

Effect of Treatment on Academic Performance

Problems with school performance is a common reason that children receive treatment for ADHD, yet the literature on the long-term impact of stimulant treatment on ADHD is mixed, with stronger evidence for short-term than for long-term gains.[5] Durkin and Marcus[6] designed a study to examine the effect of pharmacologic treatment on academic performance of low-income students with ADHD. Pharmacologic treatment included all classes of methylphenidate (MPH), amphetamine, and pemoline. This study used de-identified Medicaid data and a District of Philadelphia database of students enrolled in public schools to evaluate children ages 6-17 years who had more than 1 prescription filled for a stimulant medication and more than 1 Medicaid claim with a clinical diagnosis of ADHD (based on International Classification of Diseases [ICD], ninth edition, Clinical Modifications 314). Exclusion criteria included children who had medical claims for a diagnosis of autism, developmental delay, mental retardation, or schizophrenia or related psychosis; in addition, patients were excluded if they had filled a prescription for atomoxetine during the marking period.

Medicaid enrollment and grade point average data were gathered from more than 2 academic grade years (grade point average measured on an unweighted scale of 0-4.0 across English, math, science, social studies) for each marking period. Adherence to therapy was measured via a stimulant medication possession ratio (MPR; defined in this study as a continuous variable ranging from 0 to 10 and calculated as the number of days of stimulant possession divided by the number of days in the marking period). In addition, based on filling of a prescription, prescription refills, and prescription claims, investigators assigned a stimulant possession status for each day in a marking period. The overall marking period was considered "stimulant adherent" if the MPR fell within a range of 0.70 or above and "stimulant nonadherent" if it was less than 0.70.

The study enrolled a total of 3532 students (76.5% male and 23.5% female; 53.8% black, 34.9% Hispanic, and 11.3% white), contributing to 29,008 marking periods across which the mean stimulant MPR was 0.312 (suggesting the dispersion of medication to cover 31.2% of calendar days for the marking period within the study). In all, 65% of the sample was classified as being in elementary school (MPR: 0.313, P < .05) and 35% as being in middle school (MPR: 0.310);19.2% of marking periods met the criteria for stimulant adherence. Within the elementary and middle school groups, a significant difference between grade point average within stimulant-adherent and stimulant- nonadherent marking periods was found (within the elementary school group: 2.20 0.63 vs 2.07 0.65; P < .001; within the middle school group: 2.14 0.84 vs 1.87 0.89; P < .001).

The association of stimulant adherence to academic performance was somewhat stronger among students with comorbid disruptive behavior disorders: stimulant adherent with disruptive behavior disorder (2.19 0.73; P < .0001) and stimulant nonadherent with disruptive behavior disorder (1.97 0.78; P < .001), and in the group of students who had not received stimulants during the 3 months before the first observed marking period. Thus, stimulant adherence was associated with higher academic grades in students with ADHD from an urban school system, providing further evidence that stimulant treatment, on average, is associated with improved school performance.

Wigal and colleagues[7] reported on the impact of stimulants on reading performance in school-age children. This study included data from a double-blind, randomized, placebo-controlled, crossover, analog classroom study evaluating 9- to 12-year-old children with ADHD. Subjects initially received open-label OROS MPH for 6 weeks, at a beginning dose of 18 mg/day with incremental increases every 3-7 days to reach an individually determined dose (maximum dose of 54 mg/day). Subjects were eligible to enter the assessment period if they had an ADHD RS-IV total and subscale score < 75th percentile for gender and age; achieved CGI-I of "very much improved" or "much improved"; or had ADHD RS-IV scores > 75th and < 85th percentiles for gender and age and CGI-I of "very much improved" or "much improved" at 54 mg/day, or at 18 or 36 mg/day because of dose reduction for tolerability. A total of 78 subjects (70.5% male and 29.5% female; 80.8% combined ADHD subtype; 19.2% inattentive subtype; and 0% hyperactivity subtype) were enrolled and 71 (91%) completed the trial.

Investigators used the Permanent Product Math Test (PERMP-Attempted) and the composite score from the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale (administered 4 hours after the stimulant dose by a classroom observer); in addition, they measured performance on the Gray Silent Reading Test (GSRT), which assesses comprehension; and the total score from the Dynamic Indicators of Basic Early Literacy Skills (DIBELS), which tests reading accuracy and speed.

As with previous analyses of the effects of stimulants in classroom settings, results indicated that subjects treated with OROS MPH achieved higher mean scores on PERMP-Attempted (P < .0001) and better behavior (lower SKAMP composite scores; P < .0001). Similarly, significantly greater improvement on the GSRT and DIBELS scores were observed in the OROS MPH treatment group when compared with placebo (91.9 vs 85.9, P = .0038 and 112.0 vs 106.2; respectively). Treatment-emergent adverse events (AEs) included decreased appetite (25.6%); upper abdominal pain (16.7%); headache (16.7%); irritability (15.4%); initial insomnia (7.7%); and dizziness, nasal congestion, and pyrexia (each at 5.1%).

The results suggest that stimulant treatment improved multiple dimensions of classroom performance, including reading accuracy and speed, reading comprehension, math performance, and classroom behaviors related to ADHD. The study is notable for its expansion of typical measures of reading skills reported in classroom studies. Moreover, the study augments limited literature exploring the impact of stimulant therapy on reading performance.

Another study[8] compared 20 mg vs 30 mg of extended-release d-isomer MPH in a randomized, double-blind, 3-period x 3-treatment, crossover study. Participants included165 children with ADHD (based on DSM-IV criteria) ages 6-12 years (mean age, 9.8 1.6 years). Subjects, who had been stabilized on MPH (40-60 mg/day) or d-MPH (20-30 mg/day) for a minimum of 2 weeks before screening, were randomly assigned to 1 of 6 treatment sequences, receiving d-MPH-ER 20 mg/day, 30 mg/day, and placebo for 7 days each. In all, 162 participants were included in the intent-to-treat analysis.

Treatment with d-MPH-ER resulted in improvements on behavioral performance and math measures through the end of the 12-hour assessment period, as seen in multiple classroom studies of long-acting stimulant treatment. Of the 185 subjects enrolled, 157 (95%) completed all treatment sequences, 8 (5%) discontinued treatment, 4 (2.4%) withdrew consent, and 4 (2.4%) did not meet protocol criteria. Data from math assessments at 10, 11, and 12 hours postdose showed that d-MPH-ER 30 mg was superior to d-MPH-ER 20 mg in both average correct (P < .01 for each timepoint) and number attempted (P < .05 at each timepoint).

AEs were reported in 28.2% of the d-MPH-ER 30-mg group, 21.5% of the d-MPH-ER 20-mg group, and 17.6% of the placebo group. The most frequently reported AEs in the d-MPH-ER 30-mg/day, d-MPH-ER 20-mg/day, and placebo groups included loss of appetite (6.1%, 4.9%, 0%, respectively); headache (4.3%, 4.3%, 1.9%, respectively); upper abdominal pain (3.7%, 3.1%, 3.1%, respectively); and insomnia (1.8%, 2.5%, 0%, respectively).

Preferential Response

It is well appreciated clinically that individuals may respond preferentially to 1 form of stimulant over another, but the differential response to different stimulant treatments has rarely been studied.[9]

Jain and colleagues[10] used data from a previously published clinical trial[11] to identify response to lisdexamfetamine (LDX) -- a lysine-linked prodrug version of dextroamphetamine -- in children who experienced an inadequate response to MPH treatment.[10] This 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel group trial used a forced-dose escalation of LDX (30, 50, or 70 mg/day) vs placebo.

Of the 290 patients, 28 were being treated with MPH at screening, 26 of whom had experienced a suboptimal response (ADHD-RS-IV total scores > 18) and participated. For 19 of the participants who had previously taken MPH, LDX treatment was associated with a mean reduction in ADHD-RS-IV total score from baseline of 24.0 12.6. Reductions in scores were similar for patients whose previous MPH dose was > 1 mg/kg and in those whose MPH dose was < 1 mg/kg.

Participants were defined as responders (30% reduction in ADHD-RS-IV total score and a CGI-I of 1 or 2 = much improved or very much improved) and remitters (ADHD-RS-IV total score < 18). Of the 26 individuals with inadequate response to MPH, 19 received active treatment with LDX. In this group, 15 (78.9%) were classified as responders and 12 of these (63.2%) were remitters; 1 patient who received placebo was also classified as a remitter. By comparison, in the overall study population of the original trial, 154 patients (72.3%) were responders and 130 (61%) were remitters. AEs in the LDX group compared with the placebo group included decreased appetite (39.0% vs 4.2%), insomnia (18.8% vs 2.2%), upper abdominal pain (11.9% vs 5.6%), headache (11.9% vs 9.7%), irritability (9.6% v. 0), weight decrease (9.2% vs 1.4%), and nausea (6.0% vs 2.8%).

The strength of any conclusions that can be drawn from this study is limited by the low sample size of subjects previously treated with MPH. Further information would be gleaned by characterization of how potency of prestudy MPH and amphetamine doses compared, with correction for the higher potency of amphetamines per milligram relative to MPH. However, this post-hoc analysis suggests that children who do not respond to MPH may respond to LDX, which is consistent with clinical experience that patients respond differently to different stimulant formulations.

Alpha-2 Adrenergic Agents

Another report[12] described longer-term results of administration of the alpha-2 adrenergic agent extended-release guanfacine (GXR)one of the newest agents to be approved for the treatment of ADHD. This study explored efficacy and safety of co-administration of GXR with stimulant therapy. Given high rates of comorbidity with ADHD and the fact that some patients experience a suboptimal response to monotherapy, the safety and efficacy of combination therapy is an important issue. Vince and colleagues[12] enrolled 54 subjects (ages 6 to 17 years) with ADHD in a short-term study that extended into a 2-year open-label study; 53 participants (mean age, 11.2 1.84 years; 75.5% male and 24.5% female) received at least 1 dose of GXR in combination with a psychostimulant (amphetamine or MPH). ADHD subtype included inattentive (20.8%), hyperactive/impulsive (5.7%), and combined (73.6%).

The mean baseline ADHD-RS-IV total score was 29.3 10.9, and following treatment, reductions at each visit averaged -14.7 11.6 at month 4, -19.9 10.3 at month 16, and -17.3 11.6 at month 24. The mean reduction in hyperactivity/impulsivity score and inattentiveness subscale score from baseline to endpoint, respectively, was -6.9 6.1 (P< .001) and -9.2 6.4 (P < .001). In all, 86.8% of subjects reported treatment-emergent AEs, 2 (3.8%) of which were classified as severe; 3 of the 54 (5.6%) subjects discontinued the study because of AEs. The most frequently reported AE was upper respiratory tract infection (24.5%), followed by headache (22.6%) and upper abdominal pain (15.1%). Also reported were nasopharyngitis (15.1%), decreased appetite (13.2%), irritability (13.2%), and pharyngitis (11.3%).

The mean change in pulse rate from baseline was -0.1 14.7 beats per minute. The mean change in systolic blood pressure from baseline to end of treatment was +1.2 12.4 mm Hg. The mean change in diastolic blood pressure from baseline to end of treatment was +0.9 10.0 mm Hg.

Although the open-label design of the study does not allow correction for placebo effect, the results were consistent with sustained effectiveness of the combination. Of note, no unique AEs were reported with the combination of GXR and psychostimulants compared with either class of stimulant used as monotherapy.

Adherence

Several studies have demonstrated that adherence to ADHD pharmacology is poor, as is adherence to other medical treatments. A recent study examined relative adherence to long-acting stimulants (LAS), short-acting stimulants (SAS), and atomoxetine (ATX) during the school-year period. Classi and colleagues[13] used a large US managed care database to identify 2097 children and adolescents who received prescriptions written from August 1 to October 1, 2006, and who were followed for 8 months. Adherence in this study was defined and measured by the MPR (number of days of medication supplied within interval/240 days), with a minimum of 2 claims required to calculate this ratio. Exclusion criteria included patients who had claims for multiple ADHD medications in the index window or a claim for ADHD medication 4 months before their index claim (dating back to the end of the previous school year).Of the total, 33.6% were 6-12 years old and 66.2% were 12-18 years old.

Mean MPR by medication group was similar: 171 participants on ATX therapy had a mean MPR of 0.55 0.26, 1339 participants on LAS had a mean MPR of 0.54 0.21, and 185 SAS participants had a mean MPR of 0.49 0.22. Investigators found that children were more adherent than adolescents (P < .0001) and that ADHD with hyperactivity was associated with better adherence than ADHD without hyperactivity (P < .01). Mean time to discontinuation for each group was ATX (N = 228) 96.54 80.88 days, LAS (N = 1619) 89.76 70.71 days, and SAS (N = 250) 73.38 66.58 days.

Comorbidities

Youths with ADHD often have other mental health conditions that complicate their lives. Using data from a 10-year follow-up study, Wilens and colleagues[14] explored factors that may predict substance abuse in 257 youth with ADHD (mean age, 10.70 3.04 years; 52% male) and 225 youth without ADHD (mean age, 11.79 3.24 years; 50% male). Because substance use disorders (SUDs) can be hereditary, the researchers accounted for parental history. Within the ADHD group, 46% of subjects (N = 117) had a parental history of alcohol use disorders, and 33% (N = 86) had a parental history of smoking. Within the control group, 28% (N = 64) had a parental history of alcohol use disorder and 30% (N = 68) had a parental history of smoking.

Subjects with ADHD were 1.51 times more likely to develop a SUD compared with controls (95% CI, 1.10-2.08). Comorbid oppositional defiant disorder and conduct disorder were significant predictors of SUD after adjusting for sex (hazard ratio [HR] = 2.31; z = 3.59; P < .001) and parental history of SUD (HR = 3.00; z = 4.16; P < .001). Comorbid major depressive disorder was also found to be a significant predictor in youths with drug use disorders, (HR = 2.02; z = 2.73; P = .006). Overall, gender did not predict risk for SUD, but boys who received extra help in school were less likely to develop an SUD (HR = 0.52; P = .02). In youth with ADHD, the investigators found no significant association between baseline cognitive or academic dysfunction and later SUD. Similarly, they found no significant relationship with social or family environment, or any school functioning factors, and SUD. This study did not address the relationship of SUD and treatment for ADHD.

Rubin and colleagues[15] conducted a chart review and a parental survey of children ages 6-17 years to examine treatment, and physician and parent perceptions, of patients with ADHD with or without oppositional symptoms. Children, parents, and physicians were randomly selected to participate. Oppositional symptoms were identified based on 724 physician chart reviews and parent report, as measured by items on the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L).

Parents reported a higher rate of oppositional symptoms compared with physicians reporting from chart reviews. Parents of children with ADHD and oppositional symptoms reported significantly more frequent visits, including monthly visits, for 33% of children with oppositional symptoms compared with 19% of children who did not have oppositional symptoms. With respect to treatment, 72% of parents reported that they were "extremely" or "very satisfied" with their child's medication, regardless of the presence or absence of oppositional symptoms. In addition, 72% of parents of children with oppositional symptoms and 58% of parents of children without oppositional symptoms agreed that their children's current ADHD medication was essential to the management of their symptoms. Also, 70% of parents of children with oppositional symptoms reported that medication was an "absolute necessity" for keeping order in their household, compared with 46% of parents of children without oppositional symptoms.

Ratings by parents and physicians revealed differing perceptions of oppositional symptom burden. Parents classified 45% (281) of children as having ADHD with oppositional symptoms, whereas physicians classified approximately two-thirds of this subset (185; or 29.6% of the total) as having oppositional symptoms. Moreover, a significantly greater number of parents (33%) than physicians (13%) classified their child's oppositional symptoms as severe. Parents also assigned a higher mean CPRS score (20. 0 5.1) compared with physicians (3.4 6.4; P < .05).

This study provides further evidence of the difference between physicians and parents in regard to recognition of oppositional symptoms and behaviors in patients with ADHD. Physicians appeared less likely than parents to report oppositional symptoms, and physicians attributed a lower severity to the symptoms. When it came to treatments, parents expressed a strong overall satisfaction with current treatments for oppositional symptoms plus ADHD, but as indicated by frequency of treatment requests and office visits, these children appear to face additional challenges compared with those without oppositional symptoms.

Supported by an independent educational grant from Shire.

This article is part of a CME certified activity. The complete activity is available at:http://cme.medscape.com/viewprogram/31213

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References

1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164:942-948. Abstract

2. Aydin C, Ercan ES, Kandulu R, Uslu E, Sagduyu G. ADHD in Turkish elementary school students: a two-year longitudinal study of prevalence. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-2

3. Gau SF, Shang CY. Visual memory as an endophenotype. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-20

4. Gau SF, Shang CY. Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB). J Child Psychol Psychiatry. 2010;51:838-849.

5. Powers RL, Marks DJ, Miller CJ, et al. Stimulant treatment in children with ADHD moderates adolescent academic outcome. J Child Adolesc Psychopharmacol. 2008;18:449-459. Abstract

6. Durkin M, Marcus S. Stimulant treatment and academic grades of urban children and adolescents with ADHD. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-12

7. Wigal S, Wigal T, Schuck S, et al. Effect of OROS Methylphenidate treatment on reading performance in children with ADHD. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-19.

8. Muniz R, Pestreich L, McCague K, et al. Extended-release dexmethylphenidate 30 mg improves late-day ADHD symptom control in children with ADHD: a randomized, double-blind, crossover study. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-31.

9. Pelham WE Jr, Greenslade KE, Vodde-Hamilton M, et al. Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Pediatrics. 1990;86:226-237. Abstract

10. Jain R, Babcock T, Burtea T, et al. Efficacy of lisdexamfetamine dimesylate in children with ADHD and suboptimal response to methylphenidate. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-14.

11. Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29:450-463. Abstract

12. Vince B, Sallee FR, Lyne A, Youcha S. Effects of long-term open-label co-administration of guanfacine extended release and stimulants on core symptoms of ADHD. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-24.

13. Classi P, Sugihara T, Zagar A. Adherence and persistence to medications for ADHD in children and adolescents. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-13.

14. Wilens TE, Martelon MK, Monuteaux MC, et al. What predicts substance abuse in ADHD youth? A 10-year follow-up study. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-22.

15. Rubin J, Findling R, Short EJ, et al. Differences in the diagnosis and treatment of childhood adhd patients with or without oppositional symptoms. Program and abstracts of the American Psychiatric Association 163rd Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Poster NR5-10.

Interpreting Results of New Studies in Pediatric ADHD: An Expert Interview With Robert L. Findling, MD CME

Randall F. White, MD

Posted: 07/15/2010

Editor's note :

Attention-deficit/hyperactivity disorder is one of the most common conditions that pediatricians and child psychiatrists see. Many children with this disorder respond well to typical interventions, including long-acting psychostimulants. Yet a significant number of children have complicating factors, including comorbid mental disorders and inadequate treatment response. On behalf of Medscape, Randall F. White, MD, interviewed Robert L. Findling, MD, to explore the latest thinking on this topic. Dr. Findling is Professor of Psychiatry and Pediatrics, and Director of Child and Adolescent Psychiatry, at Case Western Reserve University in Cleveland, Ohio.

Medscape: Comorbidity is common in children with attention-deficit/hyperactivity disorder (ADHD) and seems to include a variety of psychiatric disorders. Would you briefly describe what we know about the epidemiology of comorbidity in children with ADHD?

Robert L. Findling, MD: Comorbidity is the rule and not the exception, and disruptive behavior disorders are the most common conditions. These include oppositional defiant disorder (ODD) and conduct disorder. However, anxiety disorders and mood disorders are also quite common, and we know that many of these youngsters grow up to have difficulties with substance use disorders. So when faced with a youngster with ADHD, a clinician is compelled to consider the possibility of comorbidity. I should also mention that another kind of comorbidity that one needs to think about is specific learning disorders.

Medscape: ODD and oppositional behaviors, as you mentioned, are frequent in these children. A study that was presented at the 2010 annual meeting of the American Psychiatric Association (APA) in New Orleans indicated that physicians may not recognize these symptoms as often as parents do.[1] What are your comments about that study?

Dr. Findling: As a coauthor on the study, I think what it really highlights is that in this busy day and age, effective communication and understanding do not always happen. It appears that parents rate many of their children's oppositional behaviors worse than their children's physicians do. So what is going on there? Is it that physicians are minimizing it or not accurately ascertaining the behaviors? Or do the parents interpret things as oppositional that may not be quite as oppositional as they think? An example would be a youngster who is inattentive and cannot complete a task because of ADHD. A parent might see that as oppositionality, whereas a physician may just think of the failure to complete the task as a symptom of the ADHD, with disorganization and difficulty in following through.

Medscape: What are the considerations for treatment planning for children with both ADHD and ODD? Is their response to medication different from that of children without ODD?

Dr. Findling: That is a good question, and the short answer seems to be that a good place to start is to treat them as you would any youngster with ADHD. Interestingly enough, if you can effectively treat the ADHD -- and the best acute data relate to pharmacotherapy in this group of children -- it appears that the oppositional symptoms improve to a substantial degree, almost as much as the ADHD symptoms do.

Medscape: In another realm of comorbidity, a research poster presented at the APA annual meeting in New Orleans analyzed factors that are associated with the development of substance use disorders in ADHD.[2] It was a longitudinal case-control study of about 575 youth, and I would like to know your interpretation of those findings.

Dr. Findling: I think this was a useful study because it describes what many of us have feared: youngsters who have ADHD, particularly with concurrent conduct disorder symptoms, are really at risk for suboptimal outcomes. But I think what's important for us to think about is that ADHD is not just a childhood disorder. We know that these youngsters are at risk for all kinds of difficulties later on in life, and it highlights the perniciousness and pervasiveness of ADHD in many people who suffer from it.

Medscape: According to this study, comorbidity with a conduct disorder raised the risk for addiction quite a bit more than other comorbid conditions, but ODD raised the risk as well.

Dr. Findling: Yes, but then again, the youngsters with ODD are at risk of developing conduct disorder, and it doesn't surprise me that the 2 are related as conjoint risk factors. It's no surprise to find that, the more difficulties children have with conduct disorder, which might be a more malignant expression on the disruptive behavior disorder spectrum, puts these youngsters at the greatest risk for substance use disorder, another problem behavior.

Medscape: I want to talk more in depth about treatment. Approximately 70% of children with ADHD respond to treatment with the first psychostimulant trial, but a substantial minority will continue to have impairment despite treatment. In clinical practice, various factors may contribute to a poor treatment outcome. As an expert, what is your initial approach to evaluating a child who does not respond well to the initial treatment?

Dr. Findling: I think the first place to begin is always to ask if you have the correct diagnosis. Are you missing something -- is something else going psychosocially? Does the youngster need some intervention other than medicine, such as tutoring or a different school placement? Then you should think about whether the youngster is actually receiving the medicine. It's best not to have an immediate reflex to change medicines but to step back, make sure that you've got it right, and understand what role medicines may or may not have for any given youngster. But presuming that you're faced with some imperfection with medication effectiveness, what you're left with is optimizing the current medicine that the child is taking.

If that's all been done and you really have taken a thoughtful approach to this, then a general rule of thumb is to switch from one class of medicine to the next. If the youngster was receiving an amphetamine preparation, he'd be switched to a methylphenidate preparation, and vice versa. Other options that have been extensively studied include atomoxetine and extended-release guanfacine.

Medscape: To pursue that a little further, Jain and colleagues[3] presented data from a trial of lisdexamfetamine at the recent APA meeting. It was a post-hoc analysis in which 12 of 19 children who had not achieved remission with methylphenidate -- an osmotically controlled form in most cases -- remitted with the lisdexamfetamine treatment. What do you think of that study, its design, and its findings?

Dr. Findling: I think it highlights a couple of things that we know. If a patient is on a reasonable stimulant treatment and is getting suboptimal response, switching from a methylphenidate agent to an amphetamine agent seems to be useful. But I should also mention that, under the auspices of a clinical trial, youngsters are seen more frequently. We know that frequent visitations and careful monitoring can lead to improved outcomes. Therefore, although you might think that this had only to do with the medicine, you have to consider the effect of increased monitoring and more meticulous follow-up that occur in a prospective clinical trial.

Medscape: Another approach that is sometimes considered is augmenting the current medication with an additional agent, especially if there has been a partial response. What evidence do we have to guide this?

Dr. Findling: It depends on the comorbidities. If we're talking about ADHD symptoms alone, there are not a lot of randomized control trials to distinguish which approach is best. Going back to a conservative approach, are the residual symptoms of the kind that might respond to medicine? So far, there have been very little data on this, but research on extended-release guanfacine that was presented at the recent APA meeting gives an early suggestion that this may be a reasonable strategy.[4] There are concerns about the cardiovascular effects of stimulants, and guanfacine itself may have cardiovascular effects, but this study suggests a potential therapeutic benefit and at least a preliminary signal of reasonable tolerability.

Medscape: The study of extended-release guanfacine was a 9-week, uncontrolled, open-label trial in children who were already taking either methylphenidate or an amphetamine. The remission rate with the combination therapy approached 70%. Remission in this case was defined by attainment of a certain score on an ADHD rating scale, so it sounds good, but what do you think needs to be done to determine if this is a viable approach to treatment resistance?

Dr. Findling: Ultimately, the rubber hits the road in a double-blind, placebo-controlled study. Let's be clear: In a study such as the one presented at the APA meeting, patients get seen a lot more frequently, their treatments are optimized, and they may improve just by being in a study. That's why controlled trials are so important. Moreover, this was a relatively small sample size combining 2 medications that have some inherent risks. A further study with a larger sample size would be very useful to characterize not just the putative benefits, but also the risks and tolerability of the combination.

Medscape: Going back to comorbidity in relation to poor treatment response, are there certain profiles of comorbidity that might push you in one direction or another in terms of choosing the next step in pharmacotherapy?

Dr. Findling: It depends on what the condition is. For example, in the case of a youngster who is depressed and who has a history of attention problems, I'm not always capable of determining how much of the poor school performance and inattention are related to the depression vs whatever ADHD may have anteceded the episode. In most such cases, I might hold off on ADHD treatment and treat the depression, try to improve the mood, and see what is left over. In this way, you know what aspect of your care is targeting what aspect of the patient's difficulty to set expectations appropriately.

Medscape: Is there any evidence that using a psychostimulant in a child with anxiety could be counterproductive?

Dr. Findling: There is some evidence about that, and clinicians have talked about it for quite some time, but we lack definitive double-blind data to guide the best approach. In my own practice, it is something that I discuss with youngsters and their families. Interestingly enough, in many instances, I find real benefit from treating the ADHD, particularly in patients who have generalized anxiety that seems related to their inability to function as well as they'd like. The metaphor I use with families is trying to drive your car with the window fogged over. It's pretty scary. If you clean the windshield a little bit, it's a lot easier to drive and less harrowing. For many of these youngsters, treating the ADHD helps the anxiety. But there is a group of patients whose anxiety worsens with psychostimulants. Unfortunately, we can't reliably identify many of them ahead of time.

Supported by an independent educational grant from Shire.

This article is part of a CME certified activity. The complete activity is available at:http://cme.medscape.com/viewprogram/31213

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References

1. Manos M, Findling R, Short EJ, et al. Differences in the diagnosis and treatment of childhood attention-deficit/hyperactivity disorder with or without oppositional symptoms. Program and abstracts of the 163rd American Psychiatric Association Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Research poster NR5-10.

2. Wilens TE, Martelon M, Monuteaux MC, et al. What predicts substance abuse in ADHD youth: a 10-year follow-up study of boys and girls with ADHD. Program and abstracts of the 163rd American Psychiatric Association Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Research poster NR5-22.

3. Jain R, Babcock T, Burtea T, et al. Efficacy of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder and suboptimal response to methylphenidate. Program and abstracts of the 163rd American Psychiatric Association Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Research poster NR5-14.

4. Ginsberg LD, Jain R, Muphy WR, et al. Response and symptomatic remission with open-label coadministration of guanfacine extended release and stimulants for ADHD. Program and abstracts of the 163rd American Psychiatric Association Annual Meeting; May 22-26, 2010; New Orleans, Louisiana. Research poster NR3-47.

From MedscapeCME Psychiatry & Mental Health

Studies in Pediatric ADHD: Spring 2010 CME

Paul G. Hammerness, MD

Posted: 07/15/2010

The Quest for Nonpharmacologic Interventions Continues

[No authors listed] Neurofeedback for attention deficit hyperactivity disorder. Harv Ment Health Lett. 2010;26:4-5.

Summary

This review from the Harvard Mental Health Letter briefly reviews evidence on neurofeedback for attention-deficit/hyperactivity disorder (ADHD), including a recent study by Gevensleben and colleagues.[1] The analysis begins with a discussion of the long-term combined treatment study for ADHD (Multimodal Treatment Study of ADHD [MTA] study),[2] noting that initial improvements for children with ADHD are difficult to sustain and thus, families are looking for other treatment options.

In neurofeedback, brain wave patterns (via electroencephalogram) are recorded during interactive training exercises (repetitive training and positive reinforcement), which are intended to produce and reinforce brain electrical activity. A recent study conducted at the University of Gttingen, Germany[1] involved children with ADHD (not receiving medication), assigned to either a combined neurofeedback intervention (N = 59) or to an attention skills training program (N = 35). The study's primary outcome was a 25% improvement in ADHD symptoms, per parent and teacher rating. According to parent raters, 51% of children in the neurofeedback intervention responded to treatment, compared with 29% in the attention control condition. The authors report that electroencephalograph recordings in children assigned to neurofeedback training (N = 46) demonstrated a reduction in theta waves, providing support for the mechanism of action of neurofeedback.

The analysis concludes that at present, there is insufficient scientific evidence to support neurofeedback as an effective treatment option for children with ADHD.

Commentary

In the introductory section entitled "Looking for Better Options," the authors cite the MTA findings as evidence that ADHD improvements are difficult to sustain. I would emphasize that the MTA study demonstrated (using immediate-release stimulant medications) that it is difficult to sustain treatment regimens. From my clinical viewpoint, lack of sustained improvements for children with ADHD over time primarily reflects the many system impediments to effective mental health care for children in this country, not the lack of effective treatment options. However, it is appropriate to conduct scientific investigations into the efficacy and safety of ADHD treatment options being offered to families, for those who wish to use nonmedication treatments, or who don't respond to or tolerate medications.

In terms of neurofeedback itself, the scientific evidence is limited by methodological issues, eg, small sample size, lack of sufficient controls. Clinically, however, many families ask for recommendations regarding this technique. Time and financial cost are the primary risks, as well as any implicit or explicit guarantees based on successful individual cases. This German study is an advance in that it has a control arm; however, despite a low threshold definition of response (25% improvement vs the 30%-50% improvement more typical in the literature), neither neurofeedback nor the control intervention demonstrated robust effectiveness.

Alpha Agonists for ADHD +/- Oppositional Defiant Disorder

Stahl SM. Mechanism of action of alpha 2A-adrenergic agonists in attention-deficit/hyperactivity disorder with or without oppositional symptoms. J Clin Psychiatry. 2010;71:223-224.

Summary

In this clinical neuroscience update, Stephen Stahl provides a concise pictorial summary (2 pages) of the mechanism of action and theoretical clinical significance of alpha-2A adrenergic agonists. With schematics and brief blurbs, Dr. Stahl discusses how abnormal norepinephrine and dopamine activity in the prefrontal cortex may underlie ADHD, with and without comorbid oppositional defiant disorder (ODD). He discusses how the selective alpha-2A adrenergic agonist guanfacine XR can selectively target norepinephrine deficiencies.

The mechanism of action of alpha-2A adrenergic agonists may provide novel therapeutic targets for ADHD, including patients with comorbid disruptive disorders.

Commentary

The selective alpha-2A adrenergic agonist, guanfacine XR, has recently received US Food and Drug Administration (FDA) approval for ADHD. This is a long-acting form of a medication that has been used clinically for ADHD, based on a small prior literature, including in ADHD with comorbid tic disorders. Now with sufficient controlled research to support FDA approval for the ADHD indication, clinicians should be aware of the mechanism of action of this medication and consider its potential clinical utility vs the stimulant class medications; ie, a different side effect profile and potentially unique effectiveness in the setting of comorbidities.

Sudden Cardiac Death in Children With ADHD

Denchev P, Kaltman JR, Schoenbaum M, Vitiello B. Modeled economic evaluation of alternative strategies to reduce sudden cardiac death among children treated for attention deficit/hyperactivity disorder. Circulation. 2010;121:1329-1337.

Summary

The authors, under the auspices of the National Institute of Mental Health and the National Heart, Lung, and Blood Institute, examined the cost-effectiveness of pretreatment screening with electrocardiogram (ECG) for reducing sudden cardiac death risk in children with ADHD.

This article reports the cost-effectiveness of 3 screening strategies: (1) a history and physical examination, with cardiology referral if abnormal; (2) a history and physical examination plus ECG after negative history and physical examination, with cardiology referral if either is abnormal; and (3) a history and physical examination plus ECG, with cardiology referral only if ECG is abnormal. The expected incremental cost-effectiveness over strategy 1 was $39,300 for strategy 2 and $27,200 for strategy 3, per quality-adjusted life-year. Monte Carlo simulation found that the chance of incremental cost-effectiveness was 55% for strategy 2 and 71% for strategy 3 (willingness to pay $50,000 per quality-adjusted life-year). Both strategies 2 and 3 would avert 13 sudden cardiac deaths per 400,000 children before stimulant treatment for ADHD. Costs would be $1.6 million per life for strategy 2 and $1.2 million per life for strategy 3.

The authors report that adding ECG screening to pretreatment history and physical examination screening for children with ADHD provides borderline cost-effectiveness for preventing sudden cardiac death. Relative cost-effectiveness may be improved by basing cardiology referral on ECG alone.

Commentary

As the authors cite, the current practice standard is a history and physical examination, with cardiology referral if abnormal. ECG is not currently recommended as part of a routine screening of children with ADHD before medication is prescribed. This study does not change this recommendation.

The accompanying commentary[3] lauds the authors' efforts to critically examine the topic of cardiovascular safety of children with ADHD but presents concerns regarding the limitations of their approach. However, Triedman and Alexander suggest that the authors follow up with a specific study on screening before athletic participation, as the "conflation of this study with the question of sports participation confuses rather than clarifies the issue of ADHD as a standalone indication for screening."

How Does Foster Care Affect ADHD Symptoms?

Linares LO, Li M, Shrout PE, et al. The course of inattention and hyperactivity/ impulsivity symptoms after foster placement. Pediatrics. 2010;125:e489-e498.

Summary

This study examined ADHD symptoms over time after foster placement, considering parental (biologic and foster) warmth and hostility, and placement stability (number of foster-home moves and discharge from care). Children were drawn from 560 families referred consecutively from foster care agencies in New York; 19% (104 of 560) were eligible. This study included 252 maltreated children in 95 families assessed during 4 yearly waves, starting shortly after placement. Mean age was 7.8 years at study entry; the majority of children were from black or Latino minority backgrounds; all suffered from substantiated child maltreatment. Medications used by 30% of the sample were primarily psychostimulants (69%), and atypical antipsychotics (65%). ADHD diagnoses in parents ranged from 3% to 14% according to source (foster vs biologic parents), and symptom type (inattentive vs hyperactive).

Higher inattention symptoms were associated with lower parental warmth (foster parent), higher parental hostility (biologic parent, foster parent, and teacher), and discharge from care (biologic parent). Higher hyperactivity was also associated with lower parental warmth (foster parent) and higher parental hostility (biologic and foster parents), higher (average) number of foster-home moves, and discharge from care (biologic report). Higher teacher-derived hyperactivity symptoms were associated with a history of child abuse (vs neglect).

The authors concluded that ADHD symptoms can be tracked and described in the setting of foster care placement; factors including caregiving conditions may affect symptoms and trajectories. In this study, higher parental warmth (eg, acceptance, positive involvement) from foster parents and lower hostility from biologic and foster parents influenced symptom level in a positive manner, after placement.

Commentary

This report is an interesting examination of the presence and course of ADHD symptoms in a subset of children placed into foster care. It is certainly expected that such a stressor will have some impact on ADHD symptoms or the expression of any mental health condition; however, it is helpful to identify target areas for intervention in the clinical population.

The Long-term Risks for Girls With ADHD

Biederman J, Petty CR, Monuteaux MC, et al. Adult psychiatric outcomes of girls with attention deficit hyperactivity disorder: 11-year follow-up in a longitudinal case-control study. Am J Psychiatry. 2010;167:409-417.

Summary

This was a longitudinal case-control study of 6- to 18-year-old girls with (N = 140) and without (N = 122) ADHD. At 11-year follow-up, 96 (69%) of the girls with ADHD and 91 (75%) of the comparison girls were reassessed (mean age at time of 11 year follow-up = 22 years). Participants were blindly assessed with structured diagnostic interviews. Lifetime and 1-year risks for all composite categories of psychopathology were significantly greater in girls with ADHD relative to comparison girls; lifetime hazard ratios were 7.2 (95% CI = 4.0-12.7) for antisocial disorders, 6.8 (95% CI = 3.7-12.6) for mood disorders, 2.1 (95% CI = 1.6-2.9) for anxiety disorders, 3.2 (95% CI = 2.0-5.3) for developmental disorders, 2.7 (95% CI = 1.6-4.3) for addictive disorders, and 3.5 (95% CI = 1.6-7.3) for eating disorders. All composite categories remained statistically significant after controlling for other baseline psychopathology. The 1-year prevalences of composite disorders were not associated with lifetime or 1-year use of ADHD medication.

Girls with ADHD were at high risk for psychiatric comorbidities, including substance use, mood, anxiety, and eating disorders, as they entered into young adulthood. These prospective findings are in line with previous reports on boys with ADHD.

Commentary

This study offers an important window into outcomes for girls with ADHD. There are very few long-term longitudinal studies of this size and no previous reports that have followed young girls into adulthood. This study emphasizes the importance of monitoring both boys and girls with ADHD over time, for the emergence of psychopathology and associated at-risk behaviors.

ADHD and Risk for Hand Fractures

Ozer K, Gillani S, Williams A, Hak DJ. Psychiatric risk factors in pediatric hand fractures. J Pediatr Orthop. 2010;30:324-327.

Summary

This retrospective review examined psychiatric histories of 208 pediatric patients treated at a level 1 trauma center. Metacarpal fractures were the most common hand fracture seen in patients with a psychiatric history (P = .05). Notably, 52.9% (n = 18) of the patients with a positive psychiatric history had a subsequent injury, whereas only 14.6% (n = 29) of patients without a psychiatric history had a subsequent injury (P < .001). The most common psychiatric disorders were ADHD, depression, and substance abuse. Psychiatric diagnosis was significantly more frequent when the injury was due to punching compared with other mechanisms (38% vs 8%, P < .001).

The authors describe the link between pediatric hand fractures (and repeated hand injuries) and psychopathology (ADHD), and suggest that repeated hand injuries in children involving a punching mechanism may indicate the presence of psychopathology.

Commentary

In the ongoing consideration of risk for and benefit of treatment for children with ADHD, it is critical to consider the risks associated with ADHD itself, including significant bodily injury and repeat injury. Such injuries may be reduced/prevented with appropriate identification, education, and treatment of psychopathology.

Do Pesticides Cause ADHD?

Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. 2010; ePub May 17.

Summary

This study from the Departments of Environmental Health and Epidemiology, and Harvard University School of Public Health, examined the association between urinary concentrations of dialkyl phosphate (DAP) metabolites of organophosphates and pediatric ADHD.

Cross-sectional data from the National Health and Nutrition Examination Survey (2000-2004) was used to compare exposure to these pesticides and the prevalence of ADHD. The major source of exposure to organophosphate pesticides for infants and children is diet, according to the National Academy of Sciences. Children 6 to 11 years of age have the highest urinary concentrations of DAP metabolites (markers of organophosphate exposure) compared with other age groups. Six urinary DAP metabolites, resulting from the degradation of 28 different organophosphates, were measured in urine to provide an indicator of the body burden of common organophosphates.

Data were available for 1139 children, representative of the general population. A structured interview with a parent was used to ascertain ADHD diagnostic status; 119 children met the diagnostic criteria for any ADHD subtype, which corresponds to a population prevalence of 12.1% (95% CI: 9.6%-15.1%). Most children (93.8%) had 1 detectable metabolite, of the 6 DAPs measured. Children with higher urinary dialkyl phosphate concentrations, especially dimethyl alkylphosphate (DMAP) concentrations, were more likely to be diagnosed as having ADHD. A 10-fold increase in DMAP concentration was associated with an odds ratio of 1.55 (95% CI: 1.14-2.10), with adjustment for gender, age, race/ethnicity, poverty/income ratio, fasting duration, and urinary creatinine concentration. For the most-commonly detected DMAP metabolite, dimethyl thiophosphate, children with levels higher than the median of detectable concentrations had twice the odds of ADHD (adjusted odds ratio: 1.93 [95% CI: 1.23-3.02]), compared with children with undetectable levels.

This study finds an association between urinary DMAP metabolite concentrations (exposure to dimethyl-containing organophosphate pesticides) and higher odds of ADHD for children 8 to 15 years of age. There was a 55% to 72% increase in the odds of ADHD for a 10-fold increase in DMAP concentration.

Commentary

These findings did not identify a causal relationship. As acknowledged by the authors, the primary limitation is that DAP levels were based on the collection of only 1 urine test. Also, this is a cross-sectional analysis; children with ADHD may be more likely to be exposed because of their symptoms. More research is indicated to collect repeat samples over time, to better identify patterns of chronic exposure and perhaps the presence of important developmental windows of exposure.

The Neuroscience of ADHD

Shaw P.The shape of things to come in attention deficit hyperactivity disorder. Am J Psychiatry. 2010;167:363-365.

Summary

In this editorial, Dr Shaw, from the NIMH, discusses the ongoing efforts for a "neuroanatomic signature" of ADHD. As he mentions, previous research has identified abnormalities in volume, gray matter density, and thickness in areas such as prefrontal cortex and striatum in persons with ADHD. Dr. Shaw briefly reviews a recent work in the journal.[4] This novel study identified local surface changes in the thalamus of children with ADHD, in addition to marked volume loss in the region of the pulvinar nuclei bilaterally. The pulvinar nuclei support circuitry that detects salient somatosensory stimuli. Notably, these surface changes and associated underlying volumetric abnormalities did not lead to a change in the overall thalamic volume in youths with ADHD relative to controls. In addition, youth with ADHD who were on medication had thalamic surface morphology more closely resembling that of controls and thalamic volumes that tended to be larger than those of unmedicated youth with ADHD.

This editorial describes the good state of neuroimaging as applied to ADHD, noting the remarkable sophistication of morphologic studies, the use of novel measures of shape, complexity, volume, and thickness, in addition to examinations of white matter tracts by diffusion tensor imaging and maps of brain activation generated by functional magnetic resonance imaging.

Commentary

This editorial describes the stunning ongoing neuroscientific efforts in the field of ADHD. Not only can such investigations inform the scientific and clinical community about the underlying neurobiology of ADHD, but these efforts can continue to examine whether medication treatment is associated with "more normative brain dimensions," as suggested by the sum of the literature to date.

Supported by an independent educational grant from Shire.

This article is part of a CME certified activity. The complete activity is available at:http://cme.medscape.com/viewprogram/31213

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References

1. Gevensleben H, Holl B, Albrecht B, et al. Is neurofeedback an efficacious treatment for ADHD? A randomised controlled clinical trial. J Child Psychol Psychiatry. 2009;50:780-789. Abstract

2. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry. 2007;46:989-1002. Abstract

3. Triedman JK, Alexander ME. Needle in a haystack: modeling the incidence of sudden cardiac arrest in healthy children. Circulation. 2010;121:1283-1285. Abstract

4. Ivanov I, Bansal R, Hao X, et al. Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry. 2010;167:397-408. Abstract

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Contents of Pediatric ADHD: Advances in Research [http://cme.medscape.com/viewprogram/31213]