Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans

Sharpley, A L; Solomon, Rekha; Fernando, Alvaro; Davis, John M.; Cowen, Philip J.

doi:10.1007/bf02244239

Cited by 61 publications

(19 citation statements)

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“…The increases in slow wave sleep induced by pimavanserin were consistent with the increases in slow wave sleep induced by ritanserin 15,16,17,18 and eplivanserin 25 . The results also were consistent with a 5-HT 2A receptor mechanism underlying slow wave sleep.…”

Section: Discussionsupporting

confidence: 70%

“…Similarly, pimavanserin has been shown to increase NREM sleep in rats (unpublished observations). In humans, ritanserin, a 5-HT 2 receptor antagonist, has been shown to increase slow wave sleep in healthy volunteers after a single dose 15,16,17,18 and after repeated administration 19 . Ritanserin also increases slow wave sleep in younger 20 and older 21 poor sleepers, and in a variety of patient populations including those with depression 22 , dysthymic disorder 23 , and generalized anxiety disorder 24 .…”

Section: Introductionmentioning

confidence: 99%

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Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

et al. 2011

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Objective Determine the effects of pimavanserin tartrate [ACP-103; N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide], a selective serotonin 5-HT2A receptor inverse agonist, on slow wave sleep (SWS), other sleep parameters, and attention/vigilance. Methods Forty-five healthy adults were randomized to pimavanserin (1, 2.5, 5, or 20 mg) or placebo in a double-blind fashion (n = 9/group). Pimavanserin or placebo was administered once daily, in the morning, for 13 consecutive days. The effects of pimavanserin were measured after the first dose and again after 13 days. Sleep parameters were measured by polysomnography. Effects on attention/vigilance were measured by a continuous performance task. Results Compared to placebo, pimavanserin significantly increased SWS following single and multiple dose administration. Pimavanserin also decreased number of awakenings. PSG variables not affected by pimavanserin included sleep period time, total sleep time, sleep onset latency, number of stage shifts, total time awake, early morning wake, and microarousal index. Changes in sleep architecture parameters, sleep profile parameters, and spectral power density parameters were consistent with a selective increase in SWS. Pimavanserin did not adversely affect performance on the continuous performance test measured on the evening before or morning after polysomnography. Conclusions These data suggest that pimavanserin selectively increases slow wave sleep and decreases awakenings, an effect that does not diminish with repeated administration.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

et al. 2011

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“…The view that 5-HT, receptor antagonists should be regarded as modulators of slow-wave sleep (11) is underscored by the present results. In humans ritanserin as well as seganserin have also been shown to increase slow-wave sleep (10,17,18,26). Idzikowski et al (18) showed that ritanserin enhanced the proportion of deep slow-wave sleep, whereas Ujszaszi (31) proved that sleepiness in healthy subjects was significantly increased in parts of the day with a high sleep propensity.…”

Section: Discussionmentioning

confidence: 99%

Effects of sertindole on sleep-wake states, electroencephalogram, behavioral patterns, and epileptic activity of rats

Coenen

Ateş

Skarsfeldt

et al. 1995

Pharmacology Biochemistry and Behavior

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COENEN, A. M. L., N. ATES, T. SRARSFELDT AND E. L. J. M. VAN LUIJTELAAR. Effects of sertittdole onsleep-wake states, electroencephalogram. behavioral potterns, and epileptic activity of rats. P HARMACOL BIOCHEM BEHAV 51(2/3) 353-357, 199X-In this study we addressed the effects of the S-HT, receptor antagonist sertindole in rats.The compound was administered in doses of 0.08. 0.32, and 1.28 mg/kg, whereas a control group received the solvent. The effects of sertindole on sleep-wake states, behavioral patterns, and background electroencephalogram were studied. Following injection of drug or solvent, we recorded the electroencephalogram and electromyogram for two periods of 4 h in the dark period of the light-dark cycle on 2 successive days. On the 1st day sertindole induced a significant increase in deep slow-wave sleep, but only with a dose of 0.32 mg/kg. Furthermore, a decrease in REM sleep in alI three drug groups was established. The suppression of REM sleep was still present on the 2nd day. Sertindole also induced a decrease in alternation between behavioral patterns on the 1st day. There were no significant changes in the spectral content of the background eleetroencephalogram. In a parallel experiment it appeared that sertindole had no main effects on epileptic spike-wave discharges. This was established with a dose of 1.28 mg/kg sertindole in rats with absence seizures. These Endings suggest that sertindole. similar to other compounds modulating 5-HT, receptors, influences sleep-wake states in rats by decreasing REM sleep and mildly increasing deep slow-wave sleep, whereas behavioral variation is slightly diminished, with no effects on the background EEG and almost no effects on spike-wave discharges. (15). It has been shown in rats that compounds which particularly modulate the 5-HT2 receptor influence sleep-wake states. For example, 5.HT, antagonists such as mianserin and ritanserin increase deep slow-wave sleep, which is accompanied by a decrease of REM sleep (1 l-13). A decrease of REM sleep was not found for RP 62203, a newer 5.HT, antagonist, which also enhanced deep slow-wave sleep (28). In accordance with this it was noted that the administration of selective 5-HT uptake inhibitors gives rise to increased waking (32).A new drug with promising biologic effects is sertindole, a powerful 5-HTz receptor antagonist (25). The question put forward in this experiment was whether sertindole also has effects on sleep-wake states and furthermore, on behavioral parameters, because it is preferable that putative hypnotics should only promote sleep without affecting behavioral patterns. Also, the effects of sertindole on the spectral content of the background electroencephalogram (EEG) were established. Classification of drugs according to their pharmacologic EEG fingerprint is increasingly important (8,20,36).Because it is known that drugs influencing sleep-wake states may also affect epileptic discharges, the putative epilepsy-modulating properties of sertindole were evaluated in a parallel experiment. This w...

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“…For example, in both rodents and humans, slow-wave sleep (SWS) is increased by the selective 5-HT 2 receptor antagonist ritanserin in a dose-dependent manner; in contrast, the selective 5-HT 2 receptor agonist meta-chlorophenylpiperazine produces the opposite effect (Idzikowski et al, 1986). Additional evidence supporting a role for 5-HT 2 receptors in sleep comes from the use of various antipsychotic agents known to promote SWS in both humans and rats (Dugovic and Wauquier, 1987;Sharpley et al, 1990;Monti and Monti, 2004). For example, the atypical antipsychotic drugs risperidone and olanzapine increase SWS in both schizophrenic and healthy subjects, respectively (Dursun et al, 1999;Sharpley et al, 2000;Yamashita et al, 2002).…”

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confidence: 99%

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Al-Shamma¹,

Anderson²,

Chuang³

et al. 2009

J Pharmacol Exp Ther

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5-Hydroxytryptamine (5-HT) 2A receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT 2A inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT 2A receptor with at least 30-and 5000-fold selectivity compared with 5-HT 2C and 5-HT 2B receptors, respectively. Nelotanserin dosed orally prevented (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT 2A agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.Serotonin has long been implicated in the regulation of sleep and wakefulness. Central serotonergic neurons of the dorsal raphe nucleus form part of the reticular activating system that innervates cortical and subcortical regions of the forebrain. As its name implies, this system modulates arousal in the central nervous system (CNS) and regulates sleep/wake states (Abrams et al., 2005). Within this system, 5-HT neurons are active during wakefulness, less active during nonrapid eye movement (NREM) sleep, and inactive during rapid eye movement (REM) sleep.5-HT activity in the CNS is mediated by multiple receptor subtypes that are classified into seven subfamilies (5-HT 1 to 5-HT 7 ) (Hoyer et al., 1994). The 5-HT 2 subfamily includes three subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C . Unlike 5-HT 2B receptors, which have limited CNS expression, 5-HT 2A and 5-HT 2C receptors are widely distributed in the CNS in areas that are implicated in the regulation of sleep and waking (Leysen, 2004). There is compelling preclinical and clinical evidence that supports a role for 5-HT 2A antagonism in the treatment of sleep maintenance insomnias (Borbély et al., This work was supported by Arena Phar...

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Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans

Cited by 61 publications

References 10 publications

Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

Effects of sertindole on sleep-wake states, electroencephalogram, behavioral patterns, and epileptic activity of rats

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

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Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans

Cited by 61 publications

References 10 publications

Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers

Effects of sertindole on sleep-wake states, electroencephalogram, behavioral patterns, and epileptic activity of rats

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

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Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia