Ritanserin Improves Sleep Quality in Narcolepsy

A recent study in narcolepsy patients has shown that ritanserin, a 5HT2-antagonist, reduced wake after sleep onset times and subjective sleepiness during daytime. To assess the efficacy of this compound in a statistically sufficient number of narcoleptic patients a double-blind, placebo-controlled, European multi-center study on the effects of ritanserin on daytime sleepiness, the feeling of being refreshed in the morning, number of unwanted sleep periods and slow-wave sleep was performed. All 134 narcolepsy patients were allowed to remain on stable concomitant antidepressant, stimulant and gammahydroxybutyrate medication during the trial. Patients were randomly assigned to treatment with 5 mg or 10 mg ritanserin or placebo given once daily for 28 days. Efficacy was measured by two 40-hour polysomnographic recordings, visual analogue scales and physician, partner, parents and patient-rated sleep-wake behavior tests prior to and after the trial. Patients kept diaries on sleepiness, numbers of wanted and unwanted sleep periods, feeling of being refreshed and frequency of narcoleptic symptoms during the entire treatment period. Treatment with 5 and 10 mg ritanserin significantly improved the ‘feeling of being refreshed in the morning,’ but no other narcoleptic symptoms as assessed in the diary. Whereas investigators had the impression that the primary efficacy parameters were not improved by ritanserin, patients reported significant improvements in four out of six parameters, and patients partners in two out of six parameters with 5 mg ritanserin compared to placebo. Both ritanserin doses resulted in a significant increase of nocturnal slow-wave sleep (percentage of total sleep time) and a significant, dose-dependent reduction in NREM stage 1 percentage during daytime sleep. The significant polysomnographic findings were not paralleled by changes in the subjective parameters daytime sleepiness or number of unplanned sleep periods. In contrast to the first study on narcoleptic patients, ritanserin only improved one subjective parameter, but did not improve objective sleep quality or number of ”sleep attacks” or reduce ”wake after sleep onset” during night or daytime sleep. In conclusion, ritanserin may serve as add-on medication for the treatment of impaired sleep quality in narcoleptic patients, but not as a stimulant or hypnotic type of medication.

Key words

Ritanserin - Narcolepsy - 40-hour polysomnographic recording - Slow-wave sleep - Visual analogue scales - Sleep quality

References

• 1 Aldrich S M. Narcolepsy.  Neurology. 1992;  42 suppl 6 4-43
• 2 American Sleep Disorders Association. ICSD - International Classification of Sleep Disorder: Diagnostic and coding manual. American Sleep Disorders Association. 1990
• 3 Awouters F, Niemegeers C JE, Megens A AHP, Meert T F, Janssen P AJ. The pharmacological profile of ritanserin, a very potent and long-acting serotonin-S2 antagonist.  Drug Dev Res. 1988;  15 61-73
• 4 Bond A, Lader M. The use of analogue scales in rating subjective feeling.  Br J Med Psychol. 1974;  47 211-8
• 5 Burton S, Eastman C, Kravitz H. Factors relating to excessive daytime sleepiness in the narcolepsy syndrome.  Sleep Res. 1988;  17 154
• 6 Broughton 1994 R, Dunham W, Weisskopf M, Rivers M. Night sleep does not predict day sleep in narcolepsy.  Electroenceph Clin Neurophysiol. 1994;  91 67-70
• 7 Broughton R. Psychosocial impact of narcolepsy-cataplexy. In Goswami M, Pollak CP, Cohen FL, Thorpy MJ, Kavey NB (eds) Psychosocial aspects of narcolepsy. New York; The Haworth Press Inc 1992: 37-43
• 8 Declerck A C, Wauquier A, Van der Ham-Veltman P HM, Gelders Y. Increase of slow-wave sleep in human volunteers by the serotonin-S2 antagonist ritanserin.  Curr Ther Res. 1987;  41 427-32
• 9 Hood B, Bruck D. Sleepiness and performance in narcolepsy.  J Sleep Res. 1996;  5 128-134
• 10 Idzikowski C, Mills F J, Glennard R. 5-Hydroxytryptamine-2 antagonist increases human slow-wave sleep.  Brain Res. 1986;  378 164-68
• 11 Idzikowski C, Cowen P J, Nutt D, Mills F J. The effects of chronic ritanserin treatment on sleep and neuro-endocrine response to L-tryptophan.  Psychopharmacology. 1987;  193 416-20
• 12 Klieser E, Strauß H. Study to establish the indication for the selective S2 antagonist ritanserin.  Pharmacopsychiat. 1988;  21 391-393
• 13 Lammers G J, Arends J, Declerck A C, Kamphuisen H AC, Schouwink G, Troost J. Ritanserin, a serotonin 5-HT2 antagonist, reduces daytime sleepiness in narcolepsy.  Sleep. 1991;  14(2) 130-32
• 14 Leysen J E, Gommeren W, Van Gompel P, Wijnants J, Heertum A HM, Janssen P FM, Laduron P M. Receptor binding properties in vitro and in vivo of ritanserin; a very potent and long-acting serotonin-S2 antagonist.  Mol Pharmacol. 1985;  27 600-11.3
• 15 Mamelak M, Scharf M B, Woods M. Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings.  Sleep. 1986;  9 (1) 285-89
• 16 Paiva T, Arriaga F, Wauquier A, Lara E, Largo R, Leitao J M. Effects of ritanserin on sleep disturbances of dysthymic patients.  Psychopharmacology. 1988;  96 395-99
• 17 Rechtschaffen A, Kales A (eds.). A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. U.S. Public Service Washington, D.C; 1968
• 18 Reyntjens A JM, Gelders Y G, Hoppengrouwers M -LJA, Vanden Bussche G. Thymosthenic effects of ritanserin (R55667), a centrally acting serotonin-S2 receptor blocker.  Drug Dev Res. 1986;  8 331-43
• 19 Scrima L, Hartman P G, Hohnson F H, Hiller F C. Efficacy of gamma-hydroxybutyrate versus placebo in the treating narcolepsy-cataplexy: double-blind subjective measures.  Biol Psychiatry. 1989;  26 331-34
• 20 Van de Velde V, Van Rooy P, Van Peer A, Woestenforghs R, Heykants J, Vanden Bussche G. Multiple-dose pharmacokinetics and dose-proportionality of ritanserin after oral administration of 5, 10 and 20 mg once daily for 7 days to healthy volunteers. Clinical Research Report (N 59 974), Janssen Parmaceutica 1987
• 21 Van Peer A, Gasparini R, Woestenborghs R, Heykants J, Gelders Y. Intravenous pharmacokinetics and effect of food on the bioavailability of ritanserin in healthy volunteers.  Naunyn-Schmiedeberg’s Arch of Pharmacol. 1985;  330(suppl.) R15
• 22 Wolf R, Dykierek P, Gattaz W F, Maras A, Kohnen R, Dittmann R W, Geuppert M, Riemann D, Berger M. Differential effects of trimipramine and fluoxetine on sleep in geriatric depression.  Pharmaocpsychiatry. 2001;  34 60-65