Abel Ickowicz

Differential Effects of Methylphenidate on Working Memory in ADHD Children with and without Comorbid Anxiety

OBJECTIVE To examine the effects of methylphenidate (MPH) on working memory and behavior in anxious and nonanxious children with attention-deficit hyperactivity disorder (ADHD). METHOD A total of 40 ADHD children (22 nonanxious, 18 anxious) completed a randomized, double-blind, placebo-controlled, crossover trial with three doses (0.3, 0.6, 0.9 mg/kg) of MPH. A serial addition task was used to assess working memory; direct observation of motor activity indexed behavior. RESULTS MPH improved working memory in the nonanxious ADHD group but not in the comorbidity anxious group. By contrast, MPH reduced activity level in both groups. The presence of concurrent learning disabilities did not influence stimulant response. CONCLUSIONS The presence of comorbid anxiety in children with ADHD predicts a less robust response to stimulant treatment and suggests that ADHD with anxiety may constitute a distinct and clinically meaningful subtype of ADHD.

Stimulant Treatment Over Five Years: Adherence, Effectiveness, and Adverse Effects

OBJECTIVE To evaluate the impact of adherence and medication status on effectiveness and adverse effects of stimulant use in children with attention-deficit/hyperactivity disorder (ADHD) over 5 years. METHOD Seventy-nine of 91 participants in a 12-month randomized controlled trial of methylphenidate and parent groups enrolled in a follow-up study. Adherence to stimulants, treatment response, and adverse effects were evaluated annually for 5 years. Changes in teacher-reported symptoms and parent-reported adverse effects were compared at 2, 3, 4, and 5 years for 3 groups: adherents, nonadherents on medication, or nonadherents off medication. Controlling for age, gender, and baseline severity, adherence status and medication status were evaluated as correlates of teacher-reported ADHD symptom scores at each year using multiple regression analyses. RESULTS At 2 years, adherents (n = 41) showed greater improvement in teacher-reported symptoms than those off medication (n = 16) and equivalent response to nonadherents on stimulants (n = 16) (p =.02). At 5 years, adherents (n = 16) showed greater improvement in teacher-reported symptoms than nonadherents on stimulants (n = 15) and those off medication (n = 14) (p =.04). At year 2 medication status (beta = 4.67 [0.40-8.95, p =.033]) and at year 5 adherence status (beta = 7.23 [3.01-11.44, p =.001]) correlated with higher teacher-reported symptom scores. Clinically significant adverse effects were present for 5 years, most commonly loss of appetite. CONCLUSIONS Psychostimulants improve ADHD symptoms for up to 5 years, but adverse effects persist.

Selective Inhibition in Children with Attention-Deficit Hyperactivity Disorder Off and On Stimulant Medication

Selective inhibition requires discrimination between auditory signals and is assessed using a modification of the stop-signal task. Selective inhibition was assessed in a group of 59 clinic-referred, DSM-IV-diagnosed children with attention-deficit hyperactivity disorder (ADHD) and compared to that of a community sample of 59 children. Methylphenidate (MPH) effects on selective inhibition were assessed in a subset of the ADHD sample that participated in an acute, randomized, placebo-controlled, crossover trial with 3 fixed doses of MPH. Children with ADHD performed more poorly than controls on the majority of selective stop-signal task parameters: they exhibited more anticipatory (invalid) responses, with less accurate and more variable responses on the response execution task, as well as a slower selective inhibition process. MPH improved speed of both inhibition and response execution processes; it also reduced variability of response execution and decreased nonselective inhibition. On the one hand, findings are consistent with purported inhibition deficit in ADHD, but on the other hand, suggest that neither the impairment itself, nor MPH effects, were restricted to inhibition.

Methylphenidate Improves Visual-Spatial Memory in Children With Attention-Deficit/Hyperactivity Disorder

OBJECTIVE To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or language problems. METHOD A clinic-referred sample of school-age children with a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial memory, planning ability, and recognition memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. MPH effects on right-handed and left-handed motor control were also assessed. RESULTS MPH significantly improved performance on a self-ordered, updating visual-spatial working memory task and on maintenance of visual-spatial information but had no effects on measures of visual-spatial planning ability or recognition memory. Also, MPH significantly improved left-handed motor control. CONCLUSIONS Beneficial effects of MPH on visual-spatial processing in ADHD are selective and restricted to visual-spatial memory.

Stop Signal and Conners' Continuous Performance Tasks: Test-Retest Reliability of Two Inhibition Measures in ADHD Children.

Objective: To measure test -retest reliability of the Stop-Signal Task (SST) and the Conners’ Continuous Performance Test (CPT) in children with ADHD. Methods: 12 children with ADHD (age 11.46 ±1.66) participated in the study. Primary outcome measures were stop-signal reaction time (SSRT) for the SST and CPT’s commission errors (%FP). For each participant, we acquired three morning (8:00am) measurements and behavioral observations, separated by two 7-day intervals. Reliability of cognitive measures and behavioral observations was measured using the Intraclass-correlation coefficient (ICC). Results: ICC values for SSRT and %FP were 0.72. Consistency of behavioral observations was much lower (ICC =0.41). Conclusion: Both the SST and the CPT yielded reliable measurements in ADHD children. Our findings lend further support to using these measures in the study of ADHD. (J. of Att. Dis. 2009; 13(2) 137-143)

Mathematical learning disorder in school-age children with attention-deficit hyperactivity disorder.

Objectives: To explore the prevalence of mathematics disorder (MD) relative to reading disorders (RD) in school-age children with attention-deficit hyperactivity disorder (ADHD) and examine the effects of age, sex, cooccurring conduct disorder (CD), and ADHD subtype on this comorbidity. Methods: Participants were school-age children (n = 476) with confirmed DSM-IV diagnosis of ADHD. The assessment included semistructured parent and teacher interviews and standardized measures of intelligence, academic attainment, and language abilities. Based on the presence or absence of concurrent learning disorders, we compared the emerging 4 groups: ADHD-only, ADHD + MD, ADHD + RD, and ADHD + MD + RD. Results: Overall prevalence of comorbid ADHD + MD was 18.1%. Age, sex, ADHD subtypes, or comorbid CD did not affect the frequency of MD. Children with concurrent ADHD and either MD or RD attained lower IQ, language, and academic scores than those with ADHD alone. Children with ADHD + MD + RD were more seriously impaired and demonstrated distinct deficits in receptive and expressive language. Conclusion: MDs are relatively common in school-age children with ADHD and are frequently associated with RDs. Children with ADHD + MD + RD are more severely impaired. These deficits simply cannot be explained as consequences of ADHD and might have unique biological underpinnings, with implications for diagnostic classification and therapeutic interventions.

Methylphenidate improves Stroop naming speed, but not response interference, in children with attention deficit hyperactivity disorder.

OBJECTIVE The goal of this study was to investigate the effect of methylphenidate (MPH) on response interference, as measured by the Stoop Color and Word Test, in children with attention deficit hyperactivity disorder (ADHD). Response interference is a core component of response inhibition that has been shown to be impaired in children with ADHD. METHODS A clinic-referred sample of school-aged children with a confirmed Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis of ADHD and good reading skills (n = 31) completed the Stroop Color and Word Test in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. RESULTS MPH did not improve response interference on the Stroop Color and Word Test but did significantly improve color naming and word naming abilities. CONCLUSION Response interference, as measured by the Stroop Color and Word Test, is not improved by MPH in children with ADHD. In addition, findings demonstrate strongly positive MPH effects on the highly effortful process of color naming, which has previously been demonstrated as impaired in children with ADHD. MPH was also shown to have a positive but smaller effect on word naming speed.

Sequence variation in the 3'-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).

The dopamine transporter gene (DAT1) has been reported to be associated with attention‐deficit hyperactivity disorder (ADHD) in a number of studies [Cook et al. (1995): Am J Human Genet 56(4):9993–998; Gill et al. (1997): Mol Psychiatry 2(4):311–313; Waldman et al. (1998): Am J Human Genet 63(6):1767–1776; Barr et al. (2001): Biol Psychiatry 49(4):333–339; Curran et al. (2001): Mol Psychiatry 6(4):425–428; Chen et al. (2003): Mol Psychiatry 8(4):393–396]. Specifically, the 10‐repeat allele of the 40‐bp variable number of tandem repeats (VNTR) polymorphism located in the 3′ untranslated region (UTR) of the gene has been found to be associated with ADHD. There is evidence from in vitro studies indicating that variability in the repeat number, and sequence variation in the 3′‐UTR of the DAT1 gene may influence the level of the dopamine transporter protein [Fuke et al. (2001): Pharmacogenomics J 1(2):152–156; Miller and Madras (2002): Mol Psychiatry 7(1):44–55]. In this study, we investigated whether DNA variation in the DAT1 3′UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. These included a MspI polymorphism (rs27072), a DraI DNA change (T/C) reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145) in addition to the VNTR. We also screened the VNTR region by direct resequencing to determine if there was sequence variation within the repeat units that could account for the association. Our results indicate that DAT1 is associated with ADHD in our sample but not with alleles of the VNTR polymorphism. We did not find any variation in the sequence for either the 10‐ or 9‐repeat alleles in the probands screened nor did we observe the reported DraI (T/C) variation. Our results therefore refute the possibility of the reported DraI variation or alleles of the VNTR as the functional variants contributing to the disorder.

Gene for the serotonin transporter and ADHD: no association with two functional polymorphisms.

Evidence from both human and animal studies implicates the serotonergic system in the development of attention‐deficit hyperactivity disorder (ADHD) including positive association studies for several key serotonergic genes. The serotonin transporter (HTT) regulates the availability of serotonin by reuptake of the neurotransmitter from the synaptic cleft. Several studies have reported an association of this gene to ADHD, specifically the long variant of a common insertion/deletion polymorphism located in the promoter of this gene that results in increased transcription and higher HTT expression. An additional study found no evidence for an association with this polymorphism. Recently, an A/G single nucleotide polymorphism (SNP) was found within the promoter polymorphism with functional studies indicating that the long variant containing the G allele at this site behaves like the short variant. This previously unidentified functional change may have confounded earlier association studies. We investigated the relationship of several variants to ADHD: the promoter polymorphisms, SNP in the 3′ untranslated region (3′UTR) with a reported association to ADHD and a rare, non‐synonymous coding SNP. These polymorphisms were genotyped in 209 ADHD families identified through an affected proband. We did not find evidence for an association of these polymorphisms, or haplotypes of these polymorphisms, to ADHD in this sample.

Association of Attention-Deficit/Hyperactivity Disorder with a Candidate Region for Reading Disabilities on Chromosome 6p

BACKGROUND Reading disabilities (RD) and attention-deficit hyperactivity/disorder (ADHD) are two common childhood disorders that co-occur by chance more often than expected. Twin studies and overlapping genetic linkage findings indicate that shared genetic factors partially contribute to this comorbidity. Linkage of ADHD to 6p, an identified RD candidate locus, has previously been reported, suggesting the possibility of a pleiotropic gene at this locus. RD has been previously associated with five genes in the region, particularly DCDC2 and KIAA0319. METHODS To test whether these genes also contribute to ADHD, we investigated markers previously associated with RD for association with ADHD and ADHD symptoms in a sample of families with ADHD (n = 264). Markers were located in two subregions, VMP/DCDC2 and KIAA0319/TTRAP. RESULTS Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. CONCLUSIONS Overall this study supports a previous linkage study of ADHD indicating a risk gene for ADHD on 6p and points to VMP or DCDC2 as the most likely candidates.