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.

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.

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.

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.

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.

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.

Effects of atomoxetine and methylphenidate on sleep in children with ADHD.

STUDY OBJECTIVES: This study compared the effects of atomoxetine and methylphenidate on the sleep of children with attention-deficit/hyperactivity disorder (ADHD). This study also compared the efficacy of these medications for treating ADHD in these children. DESIGN: Randomized, double-blind, crossover trial. SETTING: Two sleep disorders centers in the United States; 1 in a private-practice setting and 1 in a hospital setting. PATIENTS: 85 children diagnosed with ADHD. INTERVENTIONS: Twice-daily atomoxetine and thrice-daily methylphenidate, each for approximately 7 weeks. MEASUREMENTS AND RESULTS: Relative to baseline, the actigraphy data indicated that methylphenidate increased sleep-onset latency significantly more than did atomoxetine (39.2 vs 12.1 minutes, p < .001). These results were consistent with the polysomnography data. Child diaries indicated that it was easier to get up in the morning, it took less time to fall asleep, and the children slept better with atomoxetine, compared with methylphenidate. Parents reported that it was less difficult getting their children up and getting them ready in the morning and that the children were less irritable, had less difficulty getting ready for bed, and had less difficulty falling asleep with atomoxetine, compared with methylphenidate. There were no significant differences between medications using the main measures of efficacy for ADHD treatment. Atomoxetine was superior on some secondary ADHD treatment-efficacy measures, based on parent reports. The only significant differences in treatment-emergent adverse events were greater incidence of decreased appetite and greater incidence of insomnia with methylphenidate. CONCLUSIONS: Patients receiving twice-daily atomoxetine had shorter sleep-onset latencies, relative to thrice-daily methylphenidate, based on objective actigraphy and polysomnography data. Although both medications decreased nighttime awakenings, the decrease was greater for methylphenidate.

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.

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.

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.

Patients with attention-deficit/hyperactivity disorder without observed apneic episodes in sleep or daytime sleepiness have normal sleep on polysomnography.

STUDY OBJECTIVE: There is continuing speculation about the relationship between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA) or periodic limb movement disorder (PLMD)/restless legs syndrome. The objective was to determine if a significant portion of children with ADHD diagnosed using DSM-IV criteria have OSA or PLMD. SETTING: Sleep disorders centers in a private practice setting and a hospital setting. PARTICIPANTS: Children aged 6 to 14 years with ADHD were enrolled. Patients with snoring were not excluded. Although patients with snoring plus either observed apneic episodes in sleep or excessive daytime sleepiness were to be excluded, as were patients with restless legs at night, only 1 subject actually had to be excluded because of these criteria. MEASUREMENTS AND RESULTS: Forty children were evaluated with a polysomnogram. A respiratory disturbance index cut-off of more than 5 per hour of sleep was used to diagnose OSA, and a periodic limb movement (with arousal) index cut-off of 5 or more per hour of sleep was used to diagnose PLMD. The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored was used to determine severity of inattentive, hyperactive, and total ADHD symptoms. Except for a somewhat longer rapid eye movement sleep latency and decreased percentage of rapid eye movement sleep, polysomnography was essentially normal. No patient had OSA or PLMD on polysomnography. CONCLUSIONS: OSA or PLMD is not a common underlying disorder or etiologic factor in patients who meet the criteria for ADHD. In the absence of symptoms suggesting a primary sleep disorder, such as snoring with observed apneic episodes in sleep or daytime sleepiness or restless legs, polysomnographic evaluation does not seem indicated in patients with ADHD.

The clinical use of the MSLT and MWT.

The studies examined in this review indicate that the MSL is sensitive to conditions expected to increase sleepiness. MSL are generally lower following sleep loss, following use of sedating medications, during wakefulness in the late night or early morning hours, and among patients with sleep disorders associated with excessive sleepiness such as narcolepsy or obstructive sleep apnea. However, the wide range in MSL makes it difficult to establish a specific threshold value for excessive sleepiness or to discriminate patients with sleep disorders from non-patients. Some of this variation may be attributable to methodological differences and some may be attributable to individual differences in sleep tendency (e.g., related to age). The studies analyzed in this review indicate that the MSL on both the MSLT and MWT does not discriminate well between patients with sleep disorders and normal populations. This is due to large SD as well as floor or ceiling effects in the tests. However, the MSL shows appropriate change from initial testing to subsequent testing following treatment or manipulations intended to alter sleepiness or alertness. Additionally the presence of two or more SOREMPs on the MSLT is a common finding in narcolepsy patients. However, SOREMPs are not exclusive to narcolepsy patients but are frequent in untreated sleep apnea

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.

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.

Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study.

OBJECTIVE: The authors assessed the efficacy of once-daily atomoxetine administration in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: In a double-blind study, children and adolescents with ADHD (N=171, age range=6-16 years) were randomly assigned to receive 6 weeks of treatment with either atomoxetine (administered once daily) or placebo. RESULTS: Outcomes among atomoxetine-treated patients were superior to those of the placebo treatment group as assessed by investigator, parent, and teacher ratings. The treatment effect size (0.71) was similar to those observed in previous atomoxetine studies that used twice-daily dosing. Parent diary ratings suggested that drug-specific effects were sustained late in the day. Discontinuations due to adverse events were low (less than 3%) for both treatment groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily administration of atomoxetine is an effective treatment for children and adolescents with ADHD.

A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of dexmethylphenidate hydrochloride (d-MPH, Focalin) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and to test an a priori hypothesis that d-MPH would have a longer duration of action than d,l-threo-methylphenidate (d,l-MPH). METHOD: This was a randomized, double-blind study conducted at 12 U.S. centers. One hundred thirty-two subjects received d-MPH (n=44), d,l-MPH (n=46), or placebo (n=42) twice daily for 4 weeks, with titration of the dose based on weekly clinic visits. The primary efficacy variable was change from baseline to last study visit on teacher-completed Swanson, Nolan, and Pelham Rating Scale (Teacher SNAP). Secondary efficacy measures included the change on parent-completed SNAP (Parent SNAP), Clinical Global Impressions Scale-Improvement (CGI-I) score, and Math Test performance. Assessments at home in late afternoon were included to test the hypothesis that d-MPH would have a longer duration of efficacy than d,l-MPH. Safety was assessed through monitoring occurrence and severity of adverse events and discontinuations related to them. RESULTS: Treatment with either d-MPH (p=.0004) or d,l-MPH (p=.0042) significantly improved Teacher SNAP ratings compared with placebo. The d-MPH group showed significant improvements compared with placebo on the afternoon Parent SNAP ratings (p=.0003) and scores on the Math Test (p=.0236) obtained late in the afternoon at 6:00 p.m. Sixty-seven percent of patients showed improvement on d-MPH and 49% on d,l-MPH based on CGI-I scores. Both d-MPH and d,l-MPH were well tolerated, no patient in the d-MPH group and only two patients each in the d,l-MPH and placebo groups discontinued the study. CONCLUSIONS: For the treatment of ADHD, an average titrated dose of 18.25 mg/day of d-MPH is as efficacious and safe as an average titrated dose of 32.14 mg/day of d,l-MPH. Both active treatments have large effect sizes. Thus, d-MPH and d,l-MPH appear to provide similar efficacy, and d-MPH may have longer duration of action after twice-daily dosing, but additional studies are needed to determine the statistical and clinical significance of this possibility.

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.