Ramelteon for Insomnia Related to Attention-Deficit/Hyperactivity Disorder (ADHD)

Abstract

Objectives: This study evaluated the efficacy of ramelteon for insomnia in adult subjects with ADHD.

Experimental design: For this randomized, double-blind, placebo-controlled crossover trial, 8 mg of ramelteon was given nightly, within three hours of bedtime, to ADHD-insomnia subjects confirmed by DSM-IV-TR, ADHD-RS, MINI, and clinical interview. All subjects underwent two weeks each of ramelteon and placebo. Objective sleep measures were obtained by actigraphy. Subjective measures included: the Epworth Sleepiness Scale (ESS) and ADHD-RS.

Principal observations: Of 36 subjects entering the study, 58% met criteria for circadian rhythm sleep disorder (CRSD), delayed sleep phase type. During ramelteon period, mid-sleep time, an indicator of circadian phase, occurred significantly earlier, by ~45 minutes compared to placebo period. An association was noted between the magnitude of the sleep phase advance and the timing of ramelteon administration in relationship to sleep start time, but did not reach statistical significance; maximal efficacy was noted 1.5 hours before bedtime. Paradoxically, ramelteon marginally, but significantly increased sleep fragmentation and ESS scores compared to the placebo state.

Conclusions: Ramelteon is efficacious in maintaining an earlier sleep/wake cycle in adults with ADHD and CRSD but can have paradoxical fragmenting effects on sleep and exacerbate daytime sleepiness. In the presence of a circadian rhythm disorder, the usual dosing and timing parameters for ramelteon need to be carefully considered.

Keywords: actigraphy; attention disorders; childhood behavioral disorder; chronobiologic treatments; circadian rhythm disorder; circadian rhythm sleep disorder; delayed sleep phase; melatonin agonists; sleep-wake schedule disorder.

Figure 1

Circadian Phase Shift as a Function of Medication Timing Relative to Bedtime. Phase Shift in Mid-Sleep Time was Calculated from The Difference Between Weeks 4 and 6 in the Placebo-Active Group. Scatter Plot Depicts the Phase Shift (in Minutes) for the Time of Ramelteon Administration per Patient. Data Were Fitted with a Smoothing Function (Using a Loess Epanechnikov Kernel Function for 80% of The Data)

Figure 2

Epworth Sleepiness Scale Scores. Bar Graph Depicting the Percentage of Subjects Within Each Treatment Group that had an Ess Score Greater than 10, A Criterion which is Commonly Used to Diagnose Excessive Daytime Sleepiness

UAB Insomnia Questionnaire

Circle each items for the last week on a scale of 0-3, 0 being absent or poor, 3 being present to maximum extent. What time would you like to go to bed on workdays? (i.e. bedtime at which you go to sleep easier and perform best the next day if going to sleep at this time?)___________________________________________________________________________ What time do you typically get in bed with the intent to sleep?___________________________________________________________________________