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 mea-sures 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.; FreeText:Sleep was assessed by both objective (actigraphy and polysomnography) and subjective (parent and child diaries) measures. Actigraphy variables included sleep-onset latency (main dependent variable), total nap time, assumed sleep time (sum of all epochs scored as sleep from sleep onset to wake time), interrupted sleep time (sum of all epochs scored as wake), number of sleep interruptions (any transition from epoch marked sleep to epoch marked wake), and total sleep interval (sleep onset to wake time, including the total duration of all sleep interruptions). Polysomnography variables included total time in bed, time to onset of first sleep epoch, time to onset of persistent sleep (defined as 20 continuous epochs of sleep), total sleep time, time in stage 1, 2, and 3/4 sleep, number of awakenings, number of arousals, time in rapid eye movement (REM) sleep, REM latency, and sleep efficiency (time asleep divided by time in bed). The parent diary included 17 items (0- to 4-point scale) and the child diary 6 items (100-mm visual analog scales). Efficacy measures included the ADHD rating Scale -IV-Parent Version: Investigator-Administered and Scored (ADHD RS), Clinical Global Impression-Severity scale, Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S), and Daily Parent Ratings of Evening and Morning Behavior (DPREMB). Safety measures included electrocardiography, systolic and diastolic blood pressure, heart rate and monocyte count.; Indications:85 patients with attention deficit hyperactivity disorder (2 hyperactive/impulsive, 25 inattentive, and 57 combined). Coexisting diseases: 41 oppositional defiant disorder, 3 conduct disorder, and 1 anxiety agoraphobia.; Patients:85 outpatients, 64 males and 21 females, age range 6-14 years (mean age 10.1 years); 62 Caucasian and 23 non-Caucasian. All patients received Ritalin and atomoxetine in a crossover fashion (41 Ritalin to atomoxetine, and 44 atomoxetine to Ritalin). Dropouts: n=10.; TypeofStudy:A randomized, double-blind, crossover, multicenter study comparing the effects of thrice daily Ritalin versus twice daily atomoxetine on the sleep of children with attention deficit hyperactivity disorder (ADHD). In addition, the efficacy and safety of the 2 drugs for the treatment of ADHD were compared.; AuthorsConclusions:In summary, these data indicate that treatment with atomoxetine was equally effective, compared to methylphenidate, in addressing core symptoms of ADHD while producing significantly fewer clinical side effects, as defined both by spontaneous reports of decreased appetite and insomnia and by objective and subjective measures of sleep and sleep quality. Patients had significantly shorter sleep-onset latencies when they were treated with atomoxetine, compared with methylphenidate, as measured by actigraphy and polysomnography. In addition, child and parent diaries suggest fewer sleep-related problems when patients were treated with atomoxetine. There is clear evidence from both experimental laboratory-based studies and clinical observations that insufficient and poor-quality sleep result in daytime sleepiness and behavioral dysregulation. Therefore, from a clinical standpoint, medication-related sleep difficulties in children with ADHD potentially have an additional negative impact on the nature and severity of daytime ADHD symptoms. Avoiding adverse effects on sleep may represent a considerable advantage for the clinician in developing effective ADHD treatment strategies. Of course, in selecting a treatment, the clinician will also consider other issues such as patient preference, ease of prescription and administration, risk of abuse, time to onset of action, and potential side effects (including fatigue, sleepiness, cardiac effects, and psychiatric effects). These issues were not examined in this study, which was designed specifically to examine effects of atomoxetine and methylphenidate on sleep.; AdverseEffects:Unspecified number of patient had sleep disorders, 19 had decreased appetite, 12 headache, 21 insomnia, decreased appetite not otherwise specified, 12 irritability, 9 unexpected therapeutic drug effect, 14 initial insomnia, 10 nasal congestion, 7 pharyngitis, 7 cough, 3 somnolence, 4 upper abdominal pain, 3 fatigue, unspecified number changes in systolic blood pressure, heart rate, temperature, RR interval, QTc interval, monocyte count, weight, laboratory analytes, and increase diastolic blood pressure.; DosageDuration:Initially 0.45 mg/kg daily tid then increased at intervals of 10 days (range, 7-12 days) to 0.9 mg/kg daily tid then 1.35 mg/kg daily tid; for patients with residual symptoms can be increased to 1.8 mg/kg daily tid. Final dose was 15-60 mg daily (mean of 42.29 mg daily) or 1.12 mg/kg daily. The morning dose was given before 8:00 AM, the midday dose at or about noon, and the afternoon dose between 4:00 and 5:00 PM. Duration: 7 weeks.; ComparativeDrug:Atomoxetine (Strattera), initially 0.5 then increased at intervals of 10 days (range, 7-12 days) to 0.8 mg/kg daily bid then 1.0 mg/kg daily bid; for patients with residual symptoms can be increased to 1.8 mg/kg daily tid. Final dose was 15-100 mg daily (mean of 58.27 mg daily) or 1.56 mg/kg daily. Duration: 7 weeks.; Results:Patient compliance ranged from 87.5% to 100% for Ritalin and from 83.3% to 100% for atomoxetine. There was a significant increase in sleep-onset latency when patients were treated with Ritalin as compared with atomoxetine (39.24 vs. 12.06 minutes). There was a significant decrease in total sleep interval more for Ritalin (-35.89 minutes) than with atomoxetine (-15.0 minutes). The number of sleep interruptions was reduced with both Ritalin and atomoxetine (-4.36 vs -1.31). Interrupted sleep time was slightly elevated for atomoxetine, compared with a small decrease for Ritalin (0.26 vs -6.28 minutes). Atomoxetine reduced assumed sleep time to a lesser extent compared to Ritalin (-15.26 vs -29.6). Ritalin produced a significantly greater increase in sleep-onset latency in patients at or below the median age and older than median age compared with atomoxetine. However, there was a significant decrease in total sleep interval, interrupted sleep time, and number of sleep interruptions more with Ritalin compared with atomoxetine in the older group only. Ritalin also produced significant greater increases in sleep-onset latency for both boys and girls compared with atomoxetine. Total sleep interval, assumed sleep time, and number of sleep interruptions were significantly reduced more with Ritalin in boys only. Polysomnography data showed that the mean time to onset of first sleep epoch was significantly increased for Ritalin than atomoxetine (16.79 vs -0.31 minutes), as was the time to onset of persistent sleep (16.81 vs -0.22 minutes). Compared to Ritalin, atomoxetine slightly increased the percentage of time in Stage 2 sleep (6% vs 3%) which correspond to an increase of 29.87 minutes with atomoxetine and 13.27 minutes with Ritalin. Similar to the actigraphy results, the number of awakenings was decreased more for Ritalin compared to atomoxetine (-6.71 vs -4.41). Wake after sleep onset was also decreased more for Ritalin compared to atomoxetine (-11.10 vs -3.62). Atomoxetine significantly increased latency to REM sleep (35.17 vs -3.55 minutes), and there was a minor decrease in the percentage of time in REM sleep with atomoxetine (- 1% vs 1% Ritalin). Although total sleep time did not differ by treatment condition, sleep efficiency was statistically increased with atomoxetine but the difference was not clinically significant. Compared with atomoxetine, Ritalin produced a significantly greater increase on the time to onset of the first sleep epoch and time to onset of persistent sleep for both at or below the median age and older than median age subgroups. Ritalin reduced total time in sleep, increased the percentage of time in REM sleep, reduced sleep efficiency, and reduced the number of awakenings in the younger patients only when compared with atomoxetine. Ritalin reduced wake time after sleep onset in the older patients only. Moreover, atomoxetine increased REM latency, compared with Ritalin, in both patient age groups. Ritalin increased time to onset of the first sleep epoch and time to onset of persistent sleep in the male patients only. In addition, Ritalin significantly reduced total time in sleep, elevated the percentage of time in REM sleep, and reduced sleep efficiency in male patients only. The number of awakenings and the amount of wake time after sleep onset were significantly decreased for Ritalin more than for atomoxetine in male patients only. Atomoxetine increased REM latency and the percentage of time in sleep Stage 2, compared with Ritalin, for the male patients only. Data from child diaries showed that it was easier to get up in the morning while they were being treated with atomoxetine, compared with Ritalin (-3.09 vs 4.51). It took less time to fall asleep with atomoxetine compared with Ritalin (-0.02 vs 13.63). Sleep was better with atomoxetine than with Ritalin (1.12 vs -4.0). Parents reported that it was less difficult getting their children out of bed when they were being treated with atomoxetine (-0.28 vs -0.03 for Ritalin). There was also a significant difference when parents reported the amount of difficulty getting their children ready in the morning (- 0.46 vs -0.22 for atomoxetine and Ritalin). Children were less irritable and less quick to lose their tempers in the morning when they were treated with atomoxetine compared to Ritalin (-0.19 vs -0.07), had less difficulty settling down and getting ready for bed (-0.35 vs -0.06), and had less difficulty falling asleep (-0.12 vs 0.41). There were no statistically significant differences between Ritalin and atomoxetine on most measures of efficacy. On the main efficacy measure, the ADHD RS Total Score, Ritalin and atomoxetine produced mean decreases of 11.79 and 13.31, respectively. There were statistically significant differences favoring atomoxetine on the DPREMB Total Score (mean change from baseline -3.65 for Ritalin vs -6.16 for atomoxetine), Evening Subscore (-2.79 vs -4.54), and Morning Subscore (-0.41 vs -1.18). 43% of patients responded to both treatments, 24% responded to atomoxetine but not Ritalin, 11% responded to Ritalin but not atomoxetine, and 23% responded to neither treatment. Of the patients who responded to atomoxetine, 64% also responded and 36% did not respond to Ritalin. Of the patients who did not respond to atomoxetine, 32% responded to Ritalin and 68% did not. Of the patients who responded to Ritalin, 80% also responded to atomoxetine and 20% did not respond to atomoxetine. Of the patients who did not respond to Ritalin, 51% responded to atomoxetine and 49% did not respond. The only statistically significant differences in treatment-emergent adverse events were higher incidence of decreased appetite and insomnia with Ritalin. There was a greater incidence of somnolence with atomoxetine. Atomoxetine produced a statistically significant elevation in diastolic blood pressure and heart rate. There was also a statistically significant difference between atomoxetine and Ritalin in the RR interval (changes from baseline -57.41 vs 16.16). Monocytes decreased more with Ritalin as compared with atomoxetine.