APD125, a selective serotonin 5-HT(2A) receptor inverse agonist, significantly improves sleep maintenance in primary insomnia.
BACKGROUND
Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT(2A) receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated.


METHODS
Adult subjects (n=173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period.


RESULTS
APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs. placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests.


CONCLUSIONS
APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia.
Rosenberg
Russell
R
NeuroTrials Research and Atlanta School of Sleep Medicine, Atlanta 30342, USA. russell.rosenberg@atlantasleep.com
Seiden
David J
DJ
Hull
Steven G
SG
Erman
Milton
M
Schwartz
Howard
H
Anderson
Christen
C
Prosser
Warren
W
Shanahan
William
W
Sanchez
Matilde
M
Chuang
Emil
E
Roth
Thomas
T
D000328:Adult; D001143:Arousal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D017286:Polysomnography / Q000187:drug effects*; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D014851:Wakefulness / Q000187:drug effects; D055815:Young Adult
D006993:Hypnotics and Sedatives; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists