The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

Baseline Lighter Sleep and Lower Saturation Are Associated With Improved Sleepiness and Adherence on Continuous Rather Than Autotitrating Positive Airway Pressure.

The objective was to test whether there were better outcomes on switching from autotitrating positive airway pressure (APAP) to continuous positive airway pressure (CPAP) in a clinic sample of patients with obstructive sleep apnea (OSA). Patients prescribed APAP in 2015-2016 and belonging to a subset characterized by side effects, or suboptimal response or adherence, were advised a switch to CPAP following a CPAP titration polysomnography. The main analysis was for improvement (after switch from APAP to CPAP) in (1) sleepiness, wakefulness inability, and fatigue, using change from baseline in the Sleepiness-Wakefulness Inability and Fatigue Test (delta SWIFT), and Epworth Sleepiness Scale (delta ESS), and (2) adherence using percentage of days with ≥4-hour use and whether there was ≥4-hour use on ≥70% days. To determine possible predictors for switching, additional analysis was performed for differences at baseline between patients switching and those staying on APAP. A total of 148 patients were switched from APAP to CPAP and had greater improvement in delta SWIFT (5.2 vs 4.1, P = .004), greater improvement in delta ESS (3.6 vs 2.9, P = .011), and better adherence (79.4% vs 74.3%, P = .006) on CPAP than on APAP. More patients were adherent on CPAP than on APAP (83.1% vs 68.9%, P = .006). Patients switching had higher baseline arousal index and stage N1 sleep, and lower nadir oxygen saturation, than 96 patients not switching. Thus, there is a subset of patients with better outcomes after switching to CPAP than on APAP. Patients with baseline lighter sleep (indicated by more arousals and stage N1), or greater desaturation, may be more likely to do better on CPAP than on APAP. CPAP may be the preferable treatment in a significant subset of patients. If APAP is used first anyway, side effects, or suboptimal response or adherence, should lead to consideration of switching to CPAP based on a CPAP titration polysomnography.

Baseline Sleep Efficiency and Arousal Index Do Not Predict Who Will Benefit From Sedatives in Improving Positive Airway Pressure Adherence in Sleep Apnea to 90.

Positive airway pressure (PAP) is the preferred treatment for obstructive sleep apnea (OSA), but adherence is low. Educational or ongoing supportive intervention improves the number of PAP adherent patients from the 50% to the 70% range. A common side effect of PAP is increased awakenings. This prospective trial examined baseline polysomnographically derived sleep efficiency and arousal index in PAP adherent and nonadherent patients, and in patients needing sedating medicines to attain PAP adherence versus those who did not need such medicines. Patients with OSA were titrated on PAP during a polysomnography or treated with autotitrating PAP, followed by educational and supportive interventions. Patients with PAP related awakenings (patients describing waking up and taking PAP off in the middle of the night) or difficulty tolerating PAP were additionally treated with medicines that suppress arousals/awakenings (trazodone, mirtazapine, doxepin). A total of 120 of 151 (79%) new patients were ≥70% PAP adherent over a continuous 30-day period, typically within the first 90 days of starting PAP, without sedating medicines. Nineteen of the remaining patients were treated with medicines that suppress arousals and awakenings, and 16 became adherent, resulting in 136 (90%) of 151 new patients achieving adherence. There were no differences in baseline sleep efficiency or arousal index, between adherent and nonadherent patients, as well as between patients who needed sedating medicines for PAP adherence and those who did not. Adding medicines that suppress arousals and awakenings for patients having trouble tolerating PAP, increases the number of patients who are PAP adherent. The need for such medicines seems to be related to the PAP side effect of increased awakenings rather than baseline impaired sleep.

Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials.

BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2. RESULTS: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.

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.

Eszopiclone for insomnia associated with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate efficacy and safety of eszopiclone compared with placebo in children and adolescents with insomnia associated with attention-deficit/hyperactivity disorder (ADHD). METHODS: A 12-week, randomized, double-blind, placebo-controlled trial evaluated efficacy and safety of high- or low-dose eszopiclone (1 or 2 mg in children aged 6-11 years, 2 or 3 mg in children ages 12-17 years), given every evening, in 486 patients with ADHD-related insomnia. The primary efficacy variable was change in latency to persistent sleep from baseline to week 12, based on polysomnography. Key secondary measures were polysomnography-measured wake time after sleep onset, Clinical Global Impression Parent/Caregiver and Child scales, and the Conners' ADHD rating scales. The safety of eszopiclone was further studied over 1 year of open-label treatment in 55 patients who completed the double-blind study, and 249 patients with no previous eszopiclone exposure. RESULTS: Neither low-dose nor high-dose eszopiclone significantly reduced latency to persistent sleep compared with placebo after 12 weeks of treatment. Secondary outcomes were considered nonsignificant based on the hierarchical statistical analysis plan. The most frequent treatment-emergent adverse events over 12 weeks with eszopiclone were headache, dysgeusia, and dizziness. The study results demonstrated that eszopiclone was well tolerated over 1 year of treatment, with 11.2% of patients discontinuing open-label treatment because of an adverse event. CONCLUSIONS: Eszopiclone (up to 3 mg) failed to reduce latency to persistent sleep on polysomnography after 12 weeks in children aged 6 to 17 years with ADHD-related insomnia. Eszopiclone was well tolerated in the 1-year study.

Evaluating sleepiness-related daytime function by querying wakefulness inability and fatigue: Sleepiness-Wakefulness Inability and Fatigue Test (SWIFT).

STUDY OBJECTIVES: Routine assessment of daytime function in Sleep Medicine has focused on "tendency to fall asleep" in soporific circumstances, to the exclusion of "wakefulness inability" or inability to maintain wakefulness, and fatigue/tiredness/lack of energy. The objective was to establish reliability and discriminant validity of a test for wakefulness inability and fatigue, and to test its superiority against the criterion standard for evaluation of sleepiness-the Epworth Sleepiness Scale (ESS). METHODS: A 12-item self-administered instrument, the Sleepiness-Wakefulness Inability and Fatigue Test (SWIFT), was developed and administered, with ESS, to 256 adults ≥ 18 years of age (44 retook the tests a month later); consecutive patients with symptoms of sleep disorders including 286 with obstructive sleep apnea ([OSA], apnea-hypopnea index ≥ 5/h sleep on polysomnography [PSG]), 49 evaluated with PSG and multiple sleep latency test for narcolepsy and 137 OSA patients treated with continuous positive airway pressure (CPAP). RESULTS: SWIFT had internal consistency 0.87 and retest intraclass coefficient 0.82. Factor analysis revealed 2 factors-general wakefulness inability and fatigue (GWIF) and driving wakefulness inability and fatigue (DWIF). Normal subjects differed from patients in ESS, SWIFT, GWIF, and DWIF. SWIFT and GWIF (but not DWIF) had higher area under ROC curve, Youden's index, and better positive and negative likelihood ratios than ESS. ESS, SWIFT, GWIF, and DWIF improved with CPAP. Improvements in SWIFT, GWIF, and DWIF (but not ESS) were significantly correlated with CPAP compliance. CONCLUSIONS: SWIFT is reliable and valid. SWIFT and its factor GWIF have a discriminant ability superior to that of the ESS.

A randomized pilot study of the efficacy and safety of ABT-089, a novel α4ß2 neuronal nicotinic receptor agonist, in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: ABT-089, an α4ß2 neuronal nicotinic receptor partial agonist (generic name pozanicline), has demonstrated efficacy in adults with attention-deficit/hyperactivity disorder (ADHD) at doses of 40 mg once daily and 40 mg twice daily. The purpose of this exploratory pilot study was to obtain initial safety, tolerability, and efficacy data for an ABT-089 80-mg once-daily regimen to inform a decision of whether to include an 80-mg once-daily dose regimen in subsequent, definitive (phase 3) efficacy studies. METHOD: This phase 2, randomized, double-blind, parallel-group, placebo-controlled pilot study was conducted at 12 sites from March to August 2008. A screening/washout period of up to 4 weeks was followed by an 8-week double-blind treatment period. Eligible subjects met DSM-IV-TR criteria for ADHD and were randomized in a 1:1:1 ratio to ABT-089 40 mg once daily, ABT-089 80 mg once daily, or placebo. The primary efficacy variable was reduction from baseline to the final evaluation in the investigator-rated Conners' Adult ADHD Rating Scale for each active treatment group versus placebo. Safety assessments and pharmacokinetic sampling were also conducted. RESULTS: A total of 160 subjects were randomized, with 137 (86%) completing the trial. No statistically significant treatment effects were observed with either ABT-089 dose for any efficacy measures. The most commonly reported adverse events in the active treatment groups were nasopharyngitis (6.6%), upper respiratory tract infection (6.6%), and somnolence (5.7%). The incidence of adverse events did not differ significantly between active groups and placebo. There were no clinically significant laboratory, electrocardiogram, or physical examination findings. CONCLUSIONS: ABT-089 was generally well tolerated at doses up to 80 mg. Because ABT-089 is a weak partial neuronal nicotinic receptor agonist, the results may not predict the potential efficacy for other, more potent neuronal nicotinic receptor agonists. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00640185.

Albuminuria and renal function in obese adults evaluated for obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with hypertension, obesity and metabolic syndrome that are risk factors for cardiovascular and chronic kidney disease. Few data are available regarding renal parameters in patients with OSA. METHODS: We conducted a cross-sectional study of 91 obese adults who had routine polysomnography before bariatric surgery. Presence and severity of OSA were determined by the apnea-hypopnea index (AHI <5 = no OSA and AHI > or = 5 = OSA). Clinical and laboratory data were available within a month of polysomnography. RESULTS: Mean +/- SD age was 44.9 +/- 9.9 years. There were 66 women. Mean +/- SD body mass index was 48.3 +/- 8.9 kg/m2 with hypertension and type 2 diabetes present in 55 and 31 subjects, respectively. There were 36 subjects with no OSA and 55 with OSA. The two groups had similar demographic characteristics, blood pressure (BP), lipid profile and medication use except for difference in mean +/- SD hemoglobin A1c (5.6 +/- 0.6% in no OSA, 6.0 +/- 0.8% in OSA; p = 0.029) and use of renin-angiotensin system blocking agents (22.2% in no OSA, 46.4% in OSA; p = 0.024). Median (interquartile range) urine albumin:creatinine ratio (ACR) was not different between the two groups [6 (4-14.5) mg/g in no OSA, 8 (5-16) mg/g in OSA; p = 0.723], while significant difference existed in serum creatinine (0.8 +/- 0.2 mg/dl in no OSA, 0.9 +/- 0.2 mg/dl in OSA, p = 0.013). Age- and gender-adjusted correlations were observed between log-log ACR and systolic BP (r = 0.265; p = 0.016), log-log ACR and diastolic BP (r = 0.245; p = 0.026) and between serum creatinine and log AHI (r = 0.188, p = 0.089). Multiple linear regression analysis demonstrated log-log ACR to be associated with diastolic BP (p = 0.046), while serum creatinine was associated with log AHI (p = 0.044). CONCLUSION: In obese adults, increasing severity of OSA is associated with higher serum creatinine but not greater degree of albuminuria.

Subjective and objective measures of sleep in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To compare objective and subjective measures of sleep in children with attention-deficit/hyperactivity disorder (ADHD) and healthy control subjects. METHODS: Included were 107 unmedicated children with ADHD and 46 healthy control subjects, all aged 6-14. Sleep-wake patterns were monitored with actigraphy for at least five consecutive days. Subjects and parents completed daily electronic diaries assessing sleep and daytime behavior. RESULTS: Actigraphy data from 80 ADHD patients and 45 control subjects showed that, compared to the healthy control group, the ADHD group experienced shorter actual sleep time (defined as time in minutes [from sleep onset to final morning awakening] of all epochs scored as sleep [i.e., excluding total duration of all epochs scored as "wake"]) (489.39 vs. 460.30min, p=.001), significantly fewer sleep interruptions (44.45 vs. 35.33, p<.001), but more total interrupted sleep time (44.49 vs. 56.70min, p=.002). Child diaries indicated children with ADHD had significantly more daytime sleepiness and difficulty getting up and less refreshing sleep. Parent diaries indicated children with ADHD had significantly more behavioral difficulties than the control group. CONCLUSIONS: Results suggest children with ADHD have reduced sleep quantity and more disturbed sleep on actigraphic measures, reduced sleep quality on the self report, and more problematic behaviors on the parent report. Clinical interventions for children with ADHD who present with sleep problems should include screening for etiologic and exacerbating factors, institution of behavioral-management strategies, and consideration of pharmacologic treatment targeted toward evening ADHD symptoms.

Cardiorespiratory fitness and obstructive sleep apnea syndrome in morbidly obese patients.

BACKGROUND: Conflicting data exist regarding the effects of obstructive sleep apnea syndrome (OSAS) on cardiorespiratory fitness in morbidly obese individuals with normal resting left ventricular function. METHODS: Ninety-two morbidly obese subjects without any prior diagnosis of OSAS underwent cardiorespiratory fitness testing, two-dimensional echocardiography, and overnight polysomnography. Using the results of the polysomnogram, comparisons were made between subjects with (n = 42) and without (n = 50) OSAS. RESULTS: Mean body mass index (BMI) for the study population (n = 92) was 48.6 +/- 9.3 kg/m(2) (+/- SD); mean age was 45.5 +/- 9.8 years, and approximately 69% were female. Despite having a higher resting, exercise, and resting mean arterial pressures, the OSAS cohort had a maximum oxygen consumption that was lower than the cohort without OSAS (21.1 mL/kg/min vs 17.6 mL/kg/min; p < 0.001). There was no difference in BMI, age, gender, waist circumference, and neck circumference between those with and without OSAS. Differences were observed between the cohorts in systolic BP, diastolic BP, and heart rate during rest, exercise, and recovery periods. There was no difference in ejection fraction, diastolic dysfunction, and treadmill test duration between cohorts. CONCLUSIONS: Morbidly obese individuals with OSAS demonstrate reduced cardiorespiratory fitness and differing hemodynamic responses to exercise testing as compared with their counterparts without this disorder. These data suggest chronic sympathetic nervous system activation negatively influences aerobic capacity in OSAS.

Cardiorespiratory fitness and sleep-related breathing disorders.

Obstructive sleep apnea and central sleep apnea are burgeoning sleep-related breathing disorders within the general population. Most of the associated comorbidities and causes of these sleep disorders are known to negatively impact cardiorespiratory fitness; however, little is known about the direct relationships between cardiorespiratory fitness, obstructive sleep apnea and central sleep apnea. This article provides a systematic analysis of existing peer reviewed, published clinical studies pertaining to the relationship between cardiorespiratory fitness and sleep-related breathing disorders in adults. A brief description of each sleep disorder, the pathophysiology, its epidemiology and its implications for cardiorespiratory fitness are provided. Finally, we discuss therapy for each disorder and its effect on the cardiovascular system.

Effects of atomoxetine on growth in children with attention-deficit/hyperactivity disorder following up to five years of treatment.

OBJECTIVE: To examine the effects on growth of long-term pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), we present findings from an ongoing 5-year study of the efficacy and safety of treatment with atomoxetine. METHODS: North American patients, 6-17 years old at study entry (N = 1,312) and with Diagnostic and Statistical Manual of Mental Disorders,4th edition (DSM-IV) ADHD, were studied under open-label atomoxetine treatment. Sixty-one were studied up to 5 years. RESULTS: After 1 month's treatment, patients weighed less than expected from their starting percentiles relative to population norms, with a maximum shortfall at 15 months and a return to expected weight by 36 months. Patients were slightly shorter than expected after 12 months, reaching a maximum shortfall at 18 months and returning to expected height by 24 months. Patients in the top quartile for body mass index (BMI) or weight at baseline, and those in the third quartile for height, showed 5-year decreases from expected values. Those below median height at baseline showed increases relative to expected values. CONCLUSIONS: These interim results indicate that continuous atomoxetine treatment for up to 5 years has little or no long-term effect on juvenile growth and final stature for most patients, although persistent decreases from expected may occur in some patients who are larger than average before treatment.

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.

Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with atomoxetine.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has its onset during childhood and is estimated to affect 3% to 7% of school-aged children. Unfortunately, the disorder frequently persists into adult life. The burden of this disorder is considerable and is often characterized by academic (or occupational) impairment and dysfunction within the family and society. Despite the existence of research demonstrating the effects of ADHD on certain aspects of life, the clinical trials of treatments for this disorder have focused primarily on efficacy and safety. METHODS: Atomoxetine was approved in the United States in November 2002 for the treatment of ADHD in children, adolescents, and adults. The present study uses data from a clinical trial of atomoxetine in adult patients with ADHD that incorporated a measure of health-related quality of life (the Medical Outcomes Study 36-item short-form health survey [SF-36]) as part of the overall assessment of the success of this relatively new treatment. The primary outcome measure for ADHD symptoms was the Conners Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS) ADHD total symptom score. RESULTS: In agreement with previous studies, adult patients with ADHD treated with atomoxetine at typical doses showed significant amelioration of ADHD symptoms, as measured on the CAARS. At baseline, the measures of overall mental health (one aspect of quality of life) of adult patients with ADHD were below the average level, as measured on the SF-36. Treatment with atomoxetine significantly improved the measures of mental health and ameliorated the ADHD symptoms. In addition, the 2 measures were correlated. CONCLUSIONS: These data suggest that pharmacological intervention with atomoxetine not only ameliorates ADHD symptoms in adult patients but also improves their perceived quality of life.

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.

A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. RESULTS: Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). CONCLUSION: Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.