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Sleep and Vigilance

, Volume 2, Issue 1, pp 23–31 | Cite as

Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man

Review
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Abstract

Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.

Keywords

Serotonin 5-HT2A inverse agonist 5-HT2A receptor antagonist N3 sleep NREM sleep REM sleep 

1 Sleep in the Normal Adult

The American Academy of Sleep Medicine [1] has broadly categorized sleep and alertness into three basic states on the basis of behavioral and physiological criteria. These are wakefulness (W), and two major types of sleep: non-rapid-eye movement (NREM) sleep and rapid-eye movement (REM) sleep. REM sleep is characterized by rapid-eye movements, muscle atonia, and desynchronized EEG patterns. NREM sleep is further subdivided into three stages; N1, N2, and N3 sleep, each corresponding to progressively deeper levels of sleep. These transitions are readily seen on a hypnogram produced from overnight polysomnographic measures. The normal adult falls asleep in the NREM N1 stage, following which sleep deepens into stages N2 and N3. These changes are marked by the appearance of spindles and slow, high-amplitude delta waves (N2), and then increasingly more numerous slow waves in stage N3, and hence, stage N3 is alternately referred to as slow wave sleep (SWS). REM sleep recurs every 90 min. The duration of SWS is greatest in children, but decreases steadily with age. Young adults spent 20–24% of a night´s sleep in stage N3 sleep (formerly “stages 3 and 4”) [2]. With advancing age changes in sleep, architecture occurs, such that the elderly spent a greater amount of time in the lighter stages of sleep (N1, N2), and less time in stage N3 [3].

2 Stage N3 Sleep, REM Sleep, and Memory Consolidation

There is evidence showing that sleep promotes memory consolidation. More specifically, however, N3 sleep and REM sleep have different roles for different types of memories. Thus, N3 sleep enhances declarative memory, whereas REM sleep is essential for procedural and emotional memories [4]. N3 sleep predominates during the first part of the night and has been demonstrated to support mainly the consolidation of hippocampus-dependent declarative memories. Conversely, REM sleep predominates during the last part of the night and has been shown to improve emotional memories involving amygdalar function, as well as procedural memories not depending on hippocampal or amygdalar function [5]. Interestingly, cortisol levels are decreased to a minimum during the first third of the night, while considerably increasing during the last third of the night. Augmenting plasma cortisol levels during N3 sleep counteracts declarative memory consolidation, but enhances emotional memory formation [5].

Thus, the damaging effects of insomnia, with its associated restriction of N3 sleep and subsequent interference with declarative memory consolidation, cannot be overstated. Several investigations have sought to explore this relationship [6]. In a polysomnographic study of patients with primary insomnia disorder, Backhaus et al. [7] found that, when compared to controls, the affected patients showed significantly less overnight consolidation of declarative memory, which was associated with reductions in N3 sleep. It has also been established that REM sleep can improve memory consolidation of new items of non-declarative information in normal subjects, whereas REM sleep loss, as well as sleep restriction and sleep fragmentation interfere with this consolidation [8]. Tests of patients who show symptoms of insomnia and a prominent decrease in N3 sleep and REM sleep fail also to show a significant overnight skill improvement in both non-conscious learning capacities (non-declarative memory) and in declarative memory tasks in which interference is imposed [9, 10]. These findings point to the importance of N3 sleep and REM sleep in protecting memory against interference when this is experimentally imposed or occurs naturally in waking experience. They further support the inference that N3 sleep and REM sleep may be largely responsible in obviating the deficits of memory impairment and performance, which are commonly described in elderly subjects [11] and in patients with a chronic insomnia disorder [10].

3 Chronic Insomnia Disorder

According to the American Psychiatric Association´s DSM-V manual [12], insomnia refers to chronic complaints of unsatisfactory sleep despite having had the opportunity to sleep. Related complaints include difficulty falling asleep, difficulty staying asleep, waking up too early, and/or not having sleep that is refreshing. Commonly occurring daytime impairments include deficits in attention, concentration and memory, as well as daytime sleepiness. The sleep disturbance and associated daytime symptoms must have occurred at least three times per week and must have been present for at least 3 months. Moreover, the sleep polysomnogram of patients suffering from an insomnia disorder shows significant reductions in N3 sleep and REM sleep. In addition, affected patients show an increased wake time after sleep onset (WASO) when compared to normal individuals [13].

4 Therapeutic Hypnotic Agents and Sleep Architecture in Patients with an Insomnia Disorder

Good practice treatment recommendations for insomnia disorders include both behavioral and pharmacological therapies. Among the several classes of medications that are included in these recommendations are the benzodiazepine (BZD) receptor allosteric modulators (either BZD (triazolam, temazepam, flurazepam) or non-BZD agents (zolpidem, eszopiclone, zaleplon), the melatonin receptor agonist ramelteon, low-dose doxepin (a tricyclic antidepressant), and the dual receptor antagonist suvorexant (Table 1). Benzodiazepine hypnotics increase the amount of stage N2 sleep while simultaneously reducing the amount of stage N3 and REM sleep [2, 14]. Non-BZD hypnotics generally do not show these reductions in N3 and REM sleep. Studies of both immediate-release or extended-release zolpidem have shown that they tend to augment N2 sleep, but do not significantly affect N3 sleep nor REM sleep in most patients [15]. Eszopiclone effects have also been studied in chronic insomnia patients. The drug was shown to significantly augment N2 sleep, although below normal levels N3 sleep and REM sleep were also observed [16]. The agent zaleplon has been shown in one polysomnographic study to produce inconsistent changes in N2 sleep, N3 sleep, and REM sleep [17]. Ramelteon has been studied in adult chronic insomniacs. In a review of thirteen trials of Ramelteon, the drug was found to reduce sleep latency and to improve sleep quality, but did not increase total sleep time (TST). Its effects of sleep architecture are generally not significant. Short-term use of the agent is associated with some parameters of improved sleep quality, but its clinical effect is small [18]. The effects of doxepin 3 and 6 mg have been studied in adult patients who met criteria for primary insomnia. The drug was associated with significant improvement in sleep maintenance and early morning awakenings, as well as increase in N2 sleep. However, the amount of time spent in REM sleep was decreased, while N3 sleep was unaffected [19]. Suvorexant is the first of a new class of medications, the dual orexin receptor antagonists that have been approved in the U.S. and Japan for the treatment of insomnia [20]. The orexins, also known as hypocretins, maintain vigilance and promote goal-directed, motivated behavior. Suvorexant´s novel mechanism of action, the blockade of both orexin receptors, interferes with the wakefulness enhancing effects of the peptide neurotransmitter [21]. In one study, the effects of suvorexant were compared to placebo in young- and middle-aged patients with chronic insomnia. The orexin antagonist was found to reduce WASO and to increase TST at the end of night 1 and at the end of week 4. The greater amounts of TST were related to an increase in REM sleep and N2 sleep [22].
Table 1

Effects of hypnotic agents on sleep induction and maintenance and sleep architecture in patients with an insomnia disorder

Variables

Benzodiazepines

Zolpidem

Eszopiclone

Zaleplon

Ramelteon

Doxepin

Suvorexant

Sleep onset latency

Decrease

Decrease

Decrease

Decrease

Decrease

No change or decrease

Decrease

Number of awakenings

Decrease

No changea

Decreaseb

Decrease

Variable effects

No change

Decrease

No change or decrease

Wake time after sleep onset

Decrease

Decreasea

Decreaseb

Decrease

No change

No change

Decrease

Decrease

Total sleep time

Increase

Inconsistenta

Increaseb

Increase

Variable effects

No change

Increase

Increase

Stage N2 sleep

Increase

Increase

Increase

Variable effects

No change

Increase

Increase

Stage N3 sleep

Decrease

No change

No change

No change

No change

No change

No change

REM sleep

Decrease

No change

No change

No change

No change

Decrease

Increase

aImmediate release

bExtended release

The currently used agents that have been applied to the treatment of chronic insomnia, and in particular to sleep onset latency (triazolam, immediate-release zolpidem, zaleplon, and ramelteon) and/or sleep maintenance (temazepam, flurazepam, zolpidem extended release, eszopiclone, and low-dose doxepin) have demonstrated efficacy for a number of sleep parameters. In general, however, these drugs fail to normalize N3 sleep and REM sleep, and in some instances actually, reduce their duration. An exception to this generalization is suvorexant, which has been shown to increase N2 sleep and REM sleep in chronic insomnia.

5 Involvement of Serotonin 5-HT2A Receptor in the Regulation of Behavioral States

The 5-HT2A receptor is involved in important waking functions such as the regulation of cognition and mood. In addition, it is involved in sleep regulation. Both preclinical and clinical studies have shown that 5-HT2 receptors modulate N3 sleep [23, 24]. There is also considerable evidence that 5-HT2A antagonism can treat sleep maintenance insomnia [25, 26]. 5-HT2A receptors which mediate the waking state are found in the dorsal raphe nucleus, locus coeruleus, ventral tegmental area, tuberomammillary nucleus, and basal forebrain. Other brain areas host 5-HT2A receptors in their sleep regulatory role. More specifically, the ventrolateral preoptic area, where these receptors are active in regulating NREM sleep, and in the laterodorsal and pedunculopontine tegmental nuclei and sublaterodorsal/precoeruleus nucleus, where receptors active in regulating REM sleep are located. Furthermore, 5-HT2A receptors have been characterized in the cerebral cortex, limbic system, and basal ganglia [27]. The importance of the 5-HT2A receptor for sleep regulation has thus led to an interest in the development of novel pharmaceutical agents which specifically antagonize the receptor or function as inverse agonists for the purpose of treating sleep disorders.

6 Sleep Patterns in Subjects with Normal Sleep and Patients with an Insomnia Disorder Administered Non-selective 5-HT2A Receptor Antagonists

Ritanserin acts as an antagonist of 5-HT2 receptors in humans, with K i values of 0.45 mM for the 5-HT2A receptor and 0.71 mM for the 5-HT2C receptor [28] (Table 2). Idzikowski et al. [29] determined for the first time the effect of acute morning administration (8.00 a.m.) of ritanserin 10 mg on nocturnal sleep in healthy subjects. The agent significantly increased N3 sleep and reduced N2 sleep and REM sleep. After 2 weeks of ritanserin treatment, N3 sleep remained augmented and N2 sleep diminished, whereas REM sleep regained control levels. All other whole-night measures remained unchanged [30]. Ketanserin behaves also as a high-affinity non-selective antagonist of 5-HT2 receptors in primates including humans (Table 2). However, the compound is a more selective antagonist of the 5-HT2A over the 5-HT2C receptor, with K i values of 2–3 nM for the 5-HT2A receptor and 130 nM for the 5-HT2C receptor [28]. Sharpley et al. [31] compared the effects of ritanserin 5 mg and ketanserin 20 mg and 40 mg on the sleep quality of healthy volunteers. Ritanserin and ketanserin 40 mg significantly increased N3 sleep and reduced N2 sleep. The effects of the 5-HT2A/2C receptor antagonists seganserin and ICI 169,369 [2-(2-dimethylaminoethylthio)-3-quinoline hydrochloride)] were studied also on the sleep EEG of subjects with normal sleep. Seganserin induced an increase of N3 sleep and an enhancement of the power density in the delta and theta frequencies during NREM sleep. In addition, intermittent W showed a reduction after drug administration [32]. Compound ICI 169,369 also induced an increase in N3 sleep [24].
Table 2

Effects of non-selective 5-HT2A receptor antagonists on sleep in healthy subjects and patients with primary or comorbid insomnia

Compound

SOL

NAW

WASO

TST

SE

N1

N2

N3

REMSL

REMS

Ketanserin

 Affinity to 5-HT2A receptor subtype

 5-HT2A: 890a

          

 5-HT2B: 540

          

 5-HT2C: 700

          

 Healthy subjects [31]

n.s.

n.s.

n.s.

n.s.

+

n.s.

n.s.

 

20–40 mg

   

40 mg

  

Ritanserin

 Affinity to 5-HT2A receptor subtype

          

 5-HT2A: 880a

          

 5-HT2B: 880

          

 5-HT2C: 890

          

 Healthy subjects [29]

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

+

n.s

      

10 mg

 

10 mg

 Middle-aged poor sleepers [33]

n.s.

n.a.

n.s.

n.a.

+

n.a.

n.s.

 

5 mg

   

5 mg

  

 Chronic primary insomnia [34]

n.s.

n.a

n.a.

n.s.

n.s.

n.s.

+

n.s.

n.s.

     

10 mg

 

10 mg

  

 Generalized anxiety disorder [36]

n.s.

n.a.

+

+

n.s.

n.s.

+

n.s.

+

  

5 mg

  

5 mg

 

5 mg

 Major depressive disorder [38]

n.s.

n.a.

n.a

+

+

n.s.

n.s.

+

n.s.

n.s.

   

5 mg

  

5 mg

  

 Abstinent alcoholic patients [35]

n.s.

n.a.

+

+

n.s.

n.s.

n.s.

n.s.

n.s.

  

10 mg

     

From: Sharpley et al. [31]; Idzikowski et al. [29]; Adam and Oswald [33]; Ruiz-Primo et al. [34]; da Roza Davis et al. [36]; Staner et al. [38]; Monti et al. [35]

SOL sleep onset latency, NAW number of awakenings, WASO wake time after sleep onset, TST total sleep time, SE sleep efficiency, N1, N2, N3 non-rapid-eye movement sleep stages, REMSL rapid-eye movement sleep latency, REMS rapid-eye movement sleep, + significant increase, − significant decrease, n.s. nonsignificant, n.a. not available

a(pK i)

In addition, ritanserin administration has shown beneficial effects on a variety of patient subgroups. They have included to poor sleepers, patients with a diagnosis of chronic insomnia disorder and psychiatric patients with a generalized anxiety disorder (GAD) or a mood disorder. Ritanserin 5 mg taken by poor sleepers for 20 days produced large and significant increases of N3 sleep during the early and the late stages of drug administration when compared with placebo. Concomitantly with the increase of N3 sleep, there was a reduction of N2 sleep and of the frequencies of awakenings [33]. The administration of ritanserin 10 mg during the morning for 5 days to a group of patients with a chronic insomnia disorder augmented the duration of N3 sleep without modifying N2 sleep or REM sleep [34]. The effect of ritanserin was characterized also in abstinent alcoholic patients with comorbid insomnia. The 5-HT2A/2C receptor antagonist was given at a daily dose of 10 mg for 28 days. Ritanserin reduced WASO and augmented TST. The increase of TST was associated with significantly greater amounts of NREM sleep. N3 sleep and REM sleep were not significantly modified [35]. Da Roza Davis et al. [36] determined the acute effects of ritanserin 5 mg on sleep variables in patients with GAD and matched healthy controls. Ritanserin administration was followed by significant increases in N3 and REM sleep together with a reduction of WASO. Polysomnographic recordings of dysthymia patients (DSM-III) who received ritanserin 10 mg for 4 weeks showed significant increases in N3 sleep [37]. Moreover, acute administration of ritanserin 5 mg in patients with a diagnosis of major depressive disorder induced significant increases in N3 sleep without changing N2 sleep or REM sleep duration [38].

In conclusion, there is substantial evidence that the non-selective 5-HT2A receptor antagonists ritanserin, ketanserin, seganserin, and ICI 169,369 consistently increase N3 sleep in subjects with normal sleep. In addition, ritanserin has been shown to augment N3 sleep in poor sleepers and patients with a chronic insomnia disorder, GAD or major depressive disorder.

7 Sleep Patterns in Subjects with Normal Sleep and Patients with an Insomnia Disorder Administered Selective 5-HT2A Receptor Antagonists and Inverse Agonists

Presently, there are a number of agents that selectively inhibit the activity of 5-HT2A receptor. These include the silent 5-HT2A receptor antagonists and inverse agonists. Studies aimed at characterizing the effects of these compounds in humans included the antagonist eplivanserin and the inverse agonists nelotanserin and pimavanserin (Table 3).
Table 3

Effects of selective 5-HT2A receptor antagonists and inverse agonists on sleep in healthy subjects and patients with chronic primary insomnia

Compound

SOL

NAW

WASO

TST

SE

N1

N2

N3

REMSL

REMS

Eplivanserin

 (selective antagonist) Affinity to 5-HT2A receptor subtype

          

 5-HT2A: 1.30a

          

 5-HT2B: n.a.

          

 5-HT2C: 120.00

          

 Healthy subjects [39]

n.s.

n.a.

n.s.

n.a.

n.s.

n.s.

+

n.s.

n.s.

      

1 mg

  

Nelotanserin

 (inverse agonist) Affinity to 5-HT2A receptor subtype

          

 5-HT2A: 0.35b

          

 5-HT2B: 2000.00

          

 5-HT2C: 100.00

          

 Healthy subjects (post-nap insomnia) [40]

n.s.

n.s.

n.s.

n.s.

+

n.s.

n.s.

 

10–40 mg

  

40 mg

 

10–40 mg

  

 Chronic primary insomnia [41]

n.s.

+

+

+

n.a.

+

 

10–40 mg

40 mg

10–40 mg

 

10 mg

Pimavanserin

 (inverse agonist) Affinity to 5-HT2A receptor subtype

          

 5-HT2A: 9.70b

          

 5-HT2B: n.a.

          

 5-HT2C: 8.00

          

 Healthy subjects [43]

n.s.

n.s.

n.s.

n.a.

n.a.

+

n.s.

n.s.

 

20 mg

    

20 mg

  

From: Landolt et al. [41]; Al-Shamma et al. [42]; Rosenberg et al. [43]; Ancoli-Israel et al. [44]

Abbreviations as in Table 2

a(plC50)

b K i values are in nanomoles

Eplivanserin has a high affinity for the 5-HT2A receptor, moderate affinity for the 5-HT2C receptor, and low affinity for the 5-HT2B receptor (Table 3). The drug is a propenone ether derivative with potent 5-HT2A receptor blocking properties and a prolonged duration of action [39]. Eplivanserin has been shown to promote sleep maintenance in rats [40]. Landolt et al. [41] investigated the effects of eplivanserin (1 mg, p.o.) on sleep EEG and power spectra in young healthy men. The compound was found to induce a significant increase in N3 sleep, while N2 sleep was reduced. Differences between placebo and the 5-HT2A receptor antagonist were not found to be significant for sleep onset latency, sleep continuity, REM sleep latency nor REM sleep in minutes. NREM sleep power within 0.75–4.5 Hz was increased, while that corresponding to spindle activity (12.5–15 Hz) was reduced. The compound did not appear to affect subjective sleep quality.

Nelotanserin is a potent, selective 5-HT2A inverse agonist. Its affinity for 5-HT2C and 5-HT2B receptors is moderate to low, respectively [42] (Table 3). In rodents, the agent has been shown to promote sleep consolidation, and to increase total NREM sleep time as well as time spent in deep sleep. Al-Shamma et al. [42] found that in a post-nap model involving healthy human subjects, the duration of N3 sleep was significantly increased following treatment with nelotanserin. All doses of nelotanserin (10, 20, 30, and 40 mg) were found to increase N3 sleep, although the most pronounced effects were observed with the 40 mg dose. In addition, a reduction in N1 sleep was observed 2–4 h after administration of the 40 mg dose. Neither sleep onset latency nor TST was affected by the treatment. In addition, the compound significantly reduced the number of awakenings and bouts of sleep and increased the duration of bouts of sleep. Furthermore, the number of stage shifts was significantly reduced, as well as the microarousal index. Analysis of EEG findings showed that most of the EEG changes occurred within the first 2–4 h after dosing [42]. The effects of nelotanserin have also been evaluated in patients with a diagnosis of chronic insomnia. The study included patients with a mean age of 45 years, who received nelotanserin (10 and 40 mg, p.o.) for 7 days. Both doses of nelotanserin significantly increased N3 sleep, whereas values corresponding to N1 and N2 sleep were reduced. In addition, following administration of the 40 mg dose, TST and sleep efficiency were significantly increased at the beginning of the treatment. By contrast, other markers of sleep efficiency were more broadly decreased: the number of awakenings and WASO, for instance, were reduced by both doses of the derivative at both timepoints [43].

Pimavanserin is a 5-HT2A receptor inverse agonist that utilizes a urea core to bridge hydrophobic and quaternary amine moieties. The agent is a potent inverse agonist at 5-HT2A receptor, while its potency is significantly less for 5-HT2C receptor and absent for 5-HT2B receptor (Table 3). Ancoli-Israel et al. [44] evaluated the effects of pimavanserin in healthy adult subjects with a mean age of 51.8 years. Pimavanserin (1, 2.5, 5 or 20 mg, p.o.) was administered in the morning for 13 consecutive days. The 20 mg dose of the derivative significantly increased N3 sleep and reduced N2 sleep throughout the administration period. Sleep onset latency, sleep continuity, and REM sleep were not affected by the compound. With respect to the spectral power, the agent significantly increased slow delta, fast delta, and theta activities and reduced spindle frequency during NREM sleep. In addition, beta activity was diminished during REM sleep.

It can be concluded that either the serotonin 5-HT2A receptor antagonist eplivanserin or the 5-HT2A receptor inverse agonists nelotanserin and pimavanserin significantly increase N3 sleep across a broad range of subjects. These include subjects with normal sleep, healthy subjects during post-nap insomnia, and patients with a chronic insomnia disorder.

8 Selective 5-HT2A Receptor Antagonists Whose Development was Discontinued

Two selective 5-HT2A receptor antagonists, namely, volinanserin and pruvanserin, have been evaluated in laboratory animals with respect to their effects on sleep variables. In one of these studies, injection of volinanserin to male mice 3 h after the beginning of the light phase of the light–dark cycle produced a significant increase in SWS during the first 3 h after administration. This compound also caused a reduction in W and REM sleep during the same period [26]. Administration of volinanserin to rats 6 h after the beginning of the dark phase significantly reduced the latency to sleep onset and W values relative to the vehicle. In addition, the 5-HT2A receptor antagonist-induced a significant increase in SWS and EEG delta power. REM sleep was not affected by the treatment [45]. Although clinical data were collected during the development program for volinanserin, the information is not publically available [46].

The effects of pruvanserin on sleep and W have been determined in the rat during both phases of the light–dark cycle. Injection of pruvanserin 2 h after the beginning of the light phase significantly increased SWS and reduced REM sleep. Administration of pruvanserin 2 h after the beginning of the dark period gave rise to a significant increase in SWS. Values corresponding to W, light sleep, and REM sleep were not significantly modified [47]. To date, no attempts have been made to characterize the effects of pruvanserin on sleep in humans.

Fananserin, which shows an affinity for serotonin 5-HT2A receptor and dopamine D4 receptor, was evaluated clinically as an antipsychotic. However, the compound failed to show efficacy for the treatment of schizophrenia, and further testing of its potential for treating insomnia disorder was never pursued.

Esmirtazapine maleate, which was in development for the treatment of an insomnia disorder, is the maleic acid salt of the S(+) enantiomer of the antidepressant drug mirtazapine. Esmirtazapine is a high-affinity antagonist at 5-HT2A and histamine H1 receptors. Ivgy-May et al. [48] administered esmirtazapine (1.5–3.0–4.5 mg) for a period of 2 weeks to non-elderly patients with a diagnosis of chronic primary insomnia. Each morning the patients completed an electronic sleep diary. All doses of the compound induced a significant increase of TST, sleep quality, and satisfaction with sleep duration. Moreover, esmirtazapine at a dose of 4.5 mg significantly reduced WASO and the number of awakenings. Ivgy-May et al. [49] determined, in addition, the effects of esmirtazapine (3.0 or 4.5 mg) administration throughout a 6-week period on sleep variables in non-elderly patients with a diagnosis of chronic primary insomnia. Polysomnographic recordings were obtained at baseline, on nights 15 and 36 and during the discontinuation period. The compound significantly reduced sleep onset latency, WASO and the number of awakenings, whereas TST, N2 sleep, and N3 sleep were increased.

9 Safety Profile of Selective 5-HT2A Receptor Antagonists and Inverse Agonists Administered to Subjects with Normal Sleep and Patients with an Insomnia Disorder

In a study of the efficacy of eplivanserin 1 mg administration to healthy volunteers, Landolt et al. [41] found no clinically meaningful changes in vital signs, hematology, coagulation, chemistry, or ECG parameters. Furthermore, Rosenberg et al. [43] reported that administration of nelotanserin 10 and 40 mg to patients with a chronic insomnia disorder did not result in changes in cognitive functions nor in motor function. In addition, there was no evidence of withdrawal effects. Moreover, Ancoli-Israel et al. [44] stated that the most frequent adverse events related to the administration of pimavanserin 20 mg were a headache and gastrointestinal discomfort. All these adverse events were mild to moderate in nature. With respect to esmirtazapine, the compound was generally well tolerated and adverse effects were mild or moderate. There were small increases in body weight in the treated patients that could depend upon the blockade of the histamine H1 receptor [48, 49].

It can be concluded that the administration of 5-HT2A receptor antagonists/inverse agonists to humans does not produce slowing nor disruption of motor coordination. In addition, treatment with these drugs was not associated with development of tolerance nor adverse effects following their abrupt withdrawal.

10 Future Treatment Options that Can Be Expected to Come Up in the Present Subject

It has been determined that selective serotonin 5-HT2A receptor antagonists and inverse agonists consistently and significantly increase N3 sleep in preclinical and clinical studies. In this respect, isolated administration of eplivanserin and pimavanserin to subjects with normal sleep and nelotanserin to healthy volunteers during a post-nap-induced insomnia significantly increased the duration of N3 sleep. A similar outcome was observed when nelotanserin was administered to patients with a chronic insomnia disorder. However, in several instances, these compounds neither decreased WASO nor increased REM sleep. How can this negative outcome be at least partly addressed in the clinical setting? A tentative strategy could be the co-administration of the 5-HT2A receptor antagonist/inverse agonist with a hypnotic drug. Relevant to this point, Griebel et al. [50] characterized the effects of eplivanserin combined with zolpidem on sleep variables in a preclinical study. The isolated administration of zolpidem (3 mg, p.o.) or eplivanserin (3 and 10 mg, p.o.) to rats did not significantly modify values corresponding to sleep and W. In contrast, the combined administration of eplivanserin and zolpidem at a dose of 3 mg/kg, p.o., respectively, induced a significant increase of SWS while W was reduced. Thus, the administration of a less than effective dose of a 5-HT2A receptor antagonist with a non-benzodiazepine GABA-A receptor allosteric modulator significantly improved sleep continuity and architecture in a preclinical study. Concerning REM sleep, it is known that the orexin receptor antagonist suvorexant increases this behavioral state in patients with an insomnia disorder. However, no attempts have been made to determine whether the combined administration of a suboptimal dose of a 5-HT2A receptor antagonists/inverse agonist with suvorexant would be followed by significant increases in both N3 sleep and REM sleep in laboratory animals.

11 Conclusion

Most patients with an insomnia disorder show significant reductions in N3 sleep and REM sleep when compared to normals. Drugs approved for the treatment of a chronic insomnia disorder are generally effective in treating the sleep initiation difficulties associated with insomnia and/or in promoting sleep maintenance. However, most currently prescribed hypnotics fail to normalize N3 sleep and REM sleep, and in some instances actually reduce their duration. It is established that when N3 sleep is reduced experimentally through N3 sleep deprivation, human subjects show increases in daytime sleep propensity as well as performance deficits and disruption of memory consolidation [43, 44]. This is particularly relevant in the case of chronic insomnia patients or in the elderly, since the reduction in N3 sleep and REM sleep that is associated with these patient groups could contribute to the deterioration of their day-to-day waking performance due to cognition and memory deficits. The evidence reviewed here suggests that 5-HT2A receptor antagonists or inverse agonists may represent a means for at least partially addressing this problem. Isolated administration of eplivanserin and pimavanserin to subjects with normal sleep and nelotanserin to healthy volunteers during post-nap-induced insomnia has been found to augment the duration of N3 sleep significantly. A similar result has been described when nelotanserin was given to patients with a chronic insomnia disorder. With one exception, none of the presently available selective 5-HT2A receptor antagonists and inverse agonists has been approved by international agencies for clinical use. Accordingly, pimavanserin was approved by the FDA (USA) on April 2016 for the treatment of hallucinations and delusions associated with Parkinson´s disease psychosis [51].

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Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics, School of Medicine Clinics HospitalUniversity of the RepublicMontevideoUruguay
  2. 2.Department of Physiology, School of MedicineUniversity of the RepublicMontevideoUruguay
  3. 3.Dufferin StreetTorontoCanada
  4. 4.Somnogen Canada IncTorontoCanada

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