Use of EEG Beta-1 Power and Theta/Beta Ratio Over Broca's Area to confirm Diagnosis of Attention Deficit/Hyperactivity Disorder in Children.

The Food and Drug Administration has approved a medical device using the electroencephalogram (EEG) theta/beta ratio (tbr) to help assess pediatric attention deficit/hyperactivity disorder (ADHD). Tbr is reported to be higher in ADHD, with increased theta and decreased beta. This study examined theta and beta-1 power differences between ADHD and normal children, during tasks of selective attention, and elucidated topographical differences. EEGs were collected from 28 normal and 58 ADHD children, aged 6 to 14 years, using 31 scalp electrodes during auditory and visual tasks requiring selective attention. Spectral analysis was performed. Tbr was higher in ADHD than in normal children (2.60 vs 2.25, P = .007), with lower beta-1 (3.66 vs 4.22, P = .01), but no difference in theta power. There was lower beta-1 (P < .001) and higher tbr (P = .002) over Broca's area (electrode locations F7 and FC5). Beta-1 power over Broca's area was the best diagnostic test, with sensitivity 0.86 and specificity 0.57. Tbr is higher and beta-1 power lower in ADHD than in normal children, especially over Broca's area. Beta-1 power and tbr assist in confirming the diagnosis of ADHD in a sample with moderate pretest probability of ADHD.

Atomoxetine improves sleepiness and global severity of illness but not the respiratory disturbance index in mild to moderate obstructive sleep apnea with sleepiness.

BACKGROUND AND PURPOSE: Norepinephrine reuptake inhibitors such as protriptyline have been shown to improve sleepiness in sleep apnea, with or without improvement in the respiratory disturbance index (RDI). This study was performed to evaluate whether the selective norepinephrine reuptake inhibitor atomoxetine improves sleepiness, the clinical global impression (CGI) of severity of illness, and the RDI in patients with mild to moderate obstructive sleep apnea with excessive sleepiness. METHODS: Patients aged 18-60 years with RDI (including apneas, hypopneas with desaturations and hypopneas with arousals) >5/h sleep, apnea-hypopnea index (AHI; including apneas, hypopneas with 4% desaturations, but not apneas with arousals) <15/h sleep, and excessive sleepiness (Epworth Sleepiness Scale [ESS]>or=10) received open-label treatment with atomoxetine 40-80 mg HS for 4 weeks, with repeat polysomnography at the end of treatment. Of 20 patients screened, 17 started treatment and 15 completed treatment. RESULTS: ESS improved from 15.3 to 10.5 and CGI improved from 4.3 to 3.1 (both significant at p<0.01), but there was no significant change in RDI. ESS and CGI improved in a linear fashion across the weeks of treatment. Sleep efficiency and % stage rapid eye movement (REM) sleep were decreased, and % stage 1, awakenings and wake after sleep onset were increased. CONCLUSIONS: Atomoxetine improved sleepiness and the CGI in patients with mild to moderate obstructive sleep apnea with sleepiness. However, it did not improve the RDI.

Attention-deficit/hyperactivity disorder: using P300 topography to choose optimal treatment.

Attention-deficit/hyperactivity disorder is the most prevalent behavioral disorder in children, and persists into adulthood. Stimulants (methylphenidate and amphetamines) with dopaminergic mechanisms are the most commonly used pharmacological treatment. Nonselective (desipramine and imipramine) and selective (atomoxetine) norepinephrine reuptake inhibitors can also be effective. What constitutes a sufficient response to treatment? Too often a partial response, leaving the patient symptomatic, is accepted. If response is defined more strictly, allowing for a return to normal, then the usually quoted 70% response rates to any given attention-deficit/hyperactivity disorder medicine drop to approximately 40%. With different medicines and not enough patients responding robustly to any given medicine, we can use medicines sequentially to find the medicine that produces a robust response. Alternatively, P300 topography can be used to select optimal treatment.

Attention-deficit/hyperactivity disorder: use of cognitive evoked potential (P300) to predict treatment response.

OBJECTIVE: To evaluate the use of P300 in predicting treatment response to medicines in patients with Attention-Deficit/Hyperactivity Disorder (ADHD), and to confirm previous reports that 31-electrode mean auditory P300 amplitude (AA) predicts response to atomoxetine; and right fronto-central to parietal AA ratio predicts response to methylphenidate. METHODS: Efficacy and P300 data from 58 children with ADHD enrolled in a double-blind crossover study using atomoxetine and methylphenidate were analyzed. Robust response was defined as 60% decrease from baseline in the ADHD rating scale. Response was alternately defined as greater than 50% decrease. RESULTS: Pre-treatment mean 31-electrode AA>6.8 microV predicted response to atomoxetine using both definitions of response. Right fronto-central to parietal AA ratio did not predict response to methylphenidate. A previous report that methylphenidate responders differed from non-responders in pre-treatment AA at T8 was confirmed, and AA at T8>7.65 microV predicted response to methylphenidate. 31-electrode mean P300 visual latency (VL) also predicted response to atomoxetine, as previously reported with imipramine. CONCLUSIONS: Mean AA predicts response to atomoxetine in ADHD patients. AA at T8 predicts response to methylphenidate. Such predictive tools may allow individually tailored choice of medicine in treatment of ADHD. SIGNIFICANCE: This allows a more informed decision of which medicine to use for a given patient.

Attention-deficit/hyperactivity disorder: cognitive evoked potential (P300) amplitude predicts treatment response to atomoxetine.

OBJECTIVE: Auditory cognitive evoked potential (P300) topography was reported to predict robust response to the stimulants pemoline and extended-release methylphenidate in patients with attention-deficit/hyperactivity disorder (ADHD). Patients with a right fronto-central to parietal auditory P300 amplitude ratio >0.5 respond robustly to stimulants, others do not. This exploratory study was performed to demonstrate whether the P300 predicts treatment response to the selective norepinephrine re-uptake inhibitor, atomoxetine. METHODS: Patients aged 6-17 with DSM-IV diagnosis of ADHD were administered P300 testing. They then underwent open-label treatment with atomoxetine. Robust response was defined as a 60% decrease from baseline in the ADHD rating scale (parent version, investigator rated). RESULTS: Ten of 17 subjects responded robustly. They did not differ from the non-robust responders in age, baseline attention or hyperactivity ratings, or any P300 parameter except 31-electrode mean auditory P300 amplitude (mean AA). Mean AA >6.8 microV predicted robust response with positive predictive value of 0.88 and negative predictive value of 0.67. CONCLUSIONS: Mean AA seems to predict response to atomoxetine in patients with ADHD. SIGNIFICANCE: As non-stimulant treatments are approved for the treatment of ADHD, tests such as this may help pinpoint whether to use a stimulant or a medicine with some other mechanism of action.

Rating scales for inattention and sleepiness are correlated in adults with symptoms of sleep disordered breathing syndrome, but not in adults with symptoms of attention-deficit/hyperactivity disorder.

BACKGROUND AND PURPOSE: To evaluate relationship between sleepiness and inattention/hyperactivity in adult patients presenting with sleepiness or early childhood onset inattention. PATIENTS AND METHODS: Thirty-eight consecutive adult patients (29 males, nine females, mean age 48.7+/-15.5 years) presenting with snoring and sleepiness; and 18 consecutive adult patients (15 males, three females, mean age 31.9+/-12.2 years) presenting with early childhood onset inattention were administered the Epworth sleepiness scale (ESS) and the attention-deficit/hyperactivity disorder rating scale (ADHDRS with AD score measuring inattention and HD score measuring hyperactivity-impulsivity). All sleepy snorers underwent polysomnography (PSG) and multiple sleep latency test (MSLT) the following day. RESULTS: For the sleepy snorers, significant correlations included AD score with ESS (r = 0.49, P = 0.002 ), and HD score with lowest saturation ( r=-0.36, P = 0.025 ). MSLT or respiratory event index (REI) were not significantly correlated with AD or HD scores or ESS. For the inattentive patients, there were no significant correlations between ESS, AD or HD score. CONCLUSIONS: Scores on rating scales for sleepiness (ESS) and inattention (AD score on the ADHDRS) are not significantly correlated in adults with early childhood onset inattention, but they are significantly correlated in sleepy snorers. Thus, in patients presenting primarily with early childhood onset inattention, sleepiness is not associated with and does not explain the inattention, even though increasing sleepiness and inattention may be associated symptoms in sleepy snorers.

Attention-deficit/hyperactivity disorder: cognitive evoked potential (P300) topography predicts treatment response to methylphenidate.

OBJECTIVE: Auditory cognitive evoked potential (P300) topography predicts robust response to the stimulant pemoline in patients with attention-deficit/hyperactivity disorder (ADHD). Patients with a right fronto-central to parietal (FC2:P4) auditory P300 amplitude ratio >0.5 respond robustly to pemoline, whereas others do not. This study was performed to demonstrate whether the same test and ratio predict treatment response to methylphenidate. METHODS: Patients aged 6-12 with DSM-IV diagnosis of ADHD were administered auditory and visual cognitive evoked potential (P300) testing. They then underwent single-blind treatment with an extended-release version of methylphenidate. Robust response was defined as a 60% decrease from baseline in a parent rated ADHD rating scale. RESULTS: Nine of 20 subjects responded robustly. They did not differ from the non-robust responders in age, baseline attention or hyperactivity ratings, or any P300 parameter except auditory P300 topography. A FC2:P4 auditory P300 amplitude ratio >0.5 predicted robust response with a positive predictive value of 0.67 and a negative predictive value of 0.73. CONCLUSIONS: The ratio of right fronto-central to parietal auditory P300 amplitude predicts response to stimulants in patients with ADHD. As non-stimulant treatments are approved for the treatment of ADHD, tests such as this may help pinpoint whether to use a stimulant or a medicine with some other mechanism of action.

What is a significant response in drug studies of attention-deficit/hyperactivity disorder: statistical significance is necessary, but is it sufficient?

The methods used to report data of clinical treatment trials can influence the interpretation of the results. Reporting that a study drug achieves a statistically significant result does not provide the absolute likelihood and magnitude of benefits. Reporting results using an absolute definition of clinical expectation from a pharmacological intervention may be useful, and characterization of placebo response may help to frame such an absolute definition. The objective of this report was to characterize placebo response in patients with attention-deficit/hyperactivity disorder (ADHD). The design was a double-blind, placebo-controlled trial of a study drug that did not produce a statistically significantly different response from placebo in a multi-center trial. Data from placebo and study drug groups at a single site were collapsed into one group to evaluate response to placebo (or ineffective drug) in a double-blind fashion. Sixty-four children aged 6 to 12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of ADHD (combined type), were enrolled; 57 completed the study. Subjects were randomized to receive either transdermal buspirone patches or matching placebo patches. Mean ADHD Rating Scale (ADHD-RS) score was 44.3 (SD 5.4) at baseline, and 37.4 (SD 10.9) after 6 weeks. Mean ratio of week 6 to baseline ADHD-RS was 0.84 (SD 0.22). Less than 5% of the sample had a 60% or greater decrease in ADHD-RS in response to placebo or ineffective medicine. A 60% decrease in the ADHD-RS seems to constitute one clear definition of clinical expectation from a pharmacological intervention, with minimal possibility of such a decrease occurring as a placebo effect.