Arianna Smerieri

New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon.

Insomnia affects 30–35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects.In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named ω1 and ω2, which are located in different areas of the CNS. The sedative action of benzodiazepines is related to ω1 receptors, whereas ω2 receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8–24 hours) and long half-life (>24 hours).The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three ‘Z’ agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with ω1 receptors (sedative effect), whereas benzodiazepines also interact with ω2 receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7–8 hours later (i.e. in the morning) generally show no relevant alterations.As with benzodiazepines, the three ‘Z’ non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.

CYCLIC ALTERNATING PATTERN (CAP) IN NORMAL SLEEP : POLYSOMNOGRAPHIC PARAMETERS IN DIFFERENT AGE GROUPS

OBJECTIVES The present study aimed at offering a standardized database for cyclic alternating pattern (CAP) parameters across representative ages of life. METHODS CAP parameters were quantified in 40 healthy sleepers and polygraphically investigated in a partially sound-proof recording chamber under a standard laboratory setting. Four age groups were investigated (teenagers: 10-19 years; young adults: 20-39 years; middle-aged: 40-59 years; elderly: 60 years). Each group included 10 subjects (5 males and 5 females). Nocturnal recordings were accomplished after adaptation to the sleep laboratory that also served to rule out the presence of sleep-related disorders. The study indicated that CAP is a natural phenomenon of NREM sleep, with specific age-related characteristics across the life cycle. RESULTS CAP rate in NREM sleep, defined as the percentage ratio of total CAP time to total NREM sleep time, showed a U-shape profile with minimum in young adults (31.9%), maximum in the elderly group (55.3%), and intermediate values in teenagers (43.4%) and in middle-aged subjects (37.5%). The longest duration of CAP cycles was found among the older subjects (31 s). The highest amounts of subtypes A1 were identified in teenagers (n = 261), while the highest amounts of A2 and A3 subtypes occurred in the elderly group (n = 183). Across the ages, the level of arousal mostly fluctuated in stages 1 and 3, whereas stage 4 emerged as the most stable NREM stage. Overall, stage 2 better reflected the CAP values referred to as total NREM sleep. CONCLUSIONS The periodic arousal fluctuations reflected by CAP are a natural phenomenon of NREM sleep with specific age-related variations across the life cycle.

CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.

OBJECTIVE Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. METHODS The PSG findings of 47 patients (18 M and 29 F, 42.5+/-10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. RESULTS Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate (P<0.0001). CONCLUSIONS PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.

Cyclic alternating pattern and spectral analysis of heart rate variability during normal sleep

The natural arousal rhythm of non‐rapid eye movement (NREM) sleep is known as the cyclic alternating pattern (CAP), which consists of arousal‐related phasic events (Phase A) that periodically interrupt the tonic theta/delta activities of NREM sleep (Phase B). The complementary condition, i.e. non‐CAP (NCAP), consists of a rhythmic electroencephalogram background with few, randomly distributed arousal‐related phasic events. Recently, some relation between CAP and autonomic function has been preliminarily reported during sleep in young adults by means of spectral analysis of heart rate variability (HRV). The present study was aimed at analysing the effects of CAP on HRV in a group of normal children and adolescents. Six normal children and adolescents (age range 10.0–17.5 y) were included in this study. All‐night polygraphic recordings were performed after adaptation to the sleep laboratory. Six 5‐min epochs were selected from sleep Stage 2 and six from Stages 3 and 4 (slow‐wave sleep), both in CAP and NCAP conditions. From such epochs, a series of parameters describing HRV was then calculated, in both time and frequency domains, on the electrocardiographic R–R intervals. Statistical comparison between CAP and NCAP epochs revealed a significant difference for most of the frequency domain parameters (increase of the low‐frequency band, increase of the low‐frequency/high‐frequency ratio and decrease in the high‐frequency band during CAP) both in Stage 2 and in slow‐wave sleep. Our results demonstrate that the physiological fluctuations of arousal during sleep described as CAP are accompanied by subtle, but significant, changes in balance between the sympathetic and vagal components of the autonomic system.

Cyclic alternating pattern (CAP) and epilepsy during sleep: how a physiological rhythm modulates a pathological event

OBJECTIVES Epileptic susceptibility is triggered by the sleeping condition. However, both ictal and interictal events are not equally affected by the different sleep states. Besides the well-known dichotomy between non-REM sleep (high activation) and REM sleep (low activation), epileptic phenomena are deeply sensitive to the ongoing level of arousal. METHODS During non-REM sleep the arousal level can be either unstable, as expressed by the repetitive sequences of the cyclic alternating pattern (CAP), or stable, as reflected by non-CAP. Phase A (arousal complex) and phase B (post-arousal rebound response) are the two basic components of the CAP cycle, which presents a 20-40 s periodicity. Three subtypes of A phases can be recognized: the A1 subtypes, which are thoroughly composed of K-complexes and delta bursts, and subtypes A2 and A3 dominated by moderate (A2) or prominent (A3) EEG desynchrony. RESULTS As a manifestation of unstable sleep, CAP offers a favorable background for the occurrence of nocturnal motor seizures that in most cases arise in concomitance with a phase A. In primary generalized epilepsy (PGE) and in lesional epilepsies with fronto-temporal focus, activation of interictal discharges is high during CAP reaching the climax during phase A and the strongest inhibition during phase B. A lack of modulation is observed instead in epilepsy with benign rolandic spikes. In PGE, the interictal bursts are mostly associated with the highly synchronized phase A1 subtypes. CONCLUSIONS The analysis of sleep microstructure based on CAP parameters offers a sensitive framework for exploring the linkage between dynamic EEG events and epileptic phenomena.

Sleep phenotypes of intellectual disability: a polysomnographic evaluation in subjects with Down syndrome and Fragile-X syndrome.

OBJECTIVE To analyze sleep architecture and NREM sleep alterations by means of the Cyclic Alternating Pattern (CAP) in children with Down syndrome (DS) and Fragile-X syndrome (fraX), the two most common causes of inherited mental retardation, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. METHODS Fourteen patients affected by fraX (mean age 13.1 years) and 9 affected by Down syndrome (mean age 13.8 years) and 26 age-matched normal controls were included. All subjects underwent overnight polysomnography in the sleep laboratory, after one adaptation night and their sleep architecture and CAP were visually scored. RESULTS FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects showed the most disrupted sleep microstructure with low total CAP rate and CAP rate in S2 NREM. Both patient groups showed a lower percentage of A1 and higher percentage of A2 and A3 compared to normal controls. CONCLUSIONS The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. SIGNIFICANCE The NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, seem to be distinctive features of intellectual disability.

CAP and arousals in the structural development of sleep: an integrative perspective

OBJECTIVES It is known that the number of arousals per hour of sleep increases linearly across life, while the amount of cyclic alternating pattern (CAP) undergoes a u-shaped evolution. The present study aimed at investigating the differences, overlaps and age-related distribution of arousals and CAP components, i.e. subtypes A1, A2, A3. The relationship between the phase A subtypes and the structural organization of sleep was also evaluated. METHODS Forty healthy subjects were examined. Polysomnographic analysis was performed according to the scoring rules for sleep stages, CAP and American Sleep Disorders Association arousals. RESULTS Arousals occurred more frequently during CAP (40 events per hour) than in total sleep time (18 events per hour), non-rapid eye movement (NREM) sleep (20 events per hour), and rapid eye movement (REM) sleep (12 events per hour). Within CAP, arousals always coincided with a subtype A2 or A3. Both arousals and subtypes A2 and A3 showed a similar evolution with relation to age (linear positive), and to the amounts of light NREM sleep (linear positive) and deep NREM sleep (linear negative). In contrast, subtypes A1 showed a u-shaped profile across the life span and appeared closely related (linear positive) to the time spent in stages 3 and 4. Almost 90% of arousals occurring in NREM sleep were preceded in the previous 3s by a K-complex or a delta burst, indicating a topical involvement of slow electroencephalographic (EEG) components in the arousal build-up. CONCLUSIONS Arousals show only one side of the multi-faceted activation complexes, whereas the three subtypes of CAP provide a graded picture of arousal features from the strongest A3 subtypes, showing a prevalence of EEG desynchrony, to the weakest A1 phases, which are dominated by EEG synchrony and represent the prevalent components of CAP (60% of all the phase A subtypes).

Quantitative analysis of sleep EEG microstructure in the time-frequency domain.

A number of phasic events influence sleep quality and sleep macrostructure. The detection of arousals and the analysis of cyclic alternating patterns (CAP) support the evaluation of sleep fragmentation and instability. Sixteen polygraphic overnight recordings were visually inspected for conventional Rechtscaffen and Kales scoring, while arousals were detected following the criteria of the American Sleep Disorders Association (ASDA). Three electroencephalograph (EEG) segments were associated to each event, corresponding to background activity, pre-arousal period and arousal. The study was supplemented by the analysis of time-frequency distribution of EEG within each subtype of phase A in the CAP. The arousals were characterized by the increase of alpha and beta power with regard to background. Within NREM sleep most of the arousals were preceded by a transient increase of delta power. The time-frequency evolution of the phase A of the CAP sequence showed a strong prevalence of delta activity during the whole A1, but high amplitude delta waves were found also in the first 2/3 s of A2 and A3, followed by desynchronization. Our results underline the strict relationship between the ASDA arousals, and the subtype A2 and A3 within the CAP: in both the association between a short sequence of transient slow waves and the successive increase of frequency and decrease of amplitude characterizes the arousal response.

CAP components and EEG synchronization in the first 3 sleep cycles.

OBJECTIVE There is consolidated evidence that stage changes in sleep are closely related to spontaneous EEG fluctuations centered on the 20-40 periodicity of the cyclic alternating pattern (CAP). The present investigation aimed at assessing the involvement of the different components of CAP in the process of build-up, maintenance and demolition of deep non-REM (NREM) sleep. METHODS CAP parameters were quantified in the first 3 sleep cycles (SC1, SC2, SC3), selected from polysomnographic recordings of 25 healthy sound sleepers belonging to an extensive age range (10-49 years). Only ideal SCs were selected, i.e. the ones uninterrupted by intervening wakefulness and in which all stages were represented and linked in a regular succession of a descending branch, a trough and an ascending branch. RESULTS Among the first 3 SCs, a total amount of 45 (SC1, 16; SC2, 13; SC3, 16) met the inclusion requirements. SCI contained the highest amount of slow wave sleep (43.7 min) and the lowest values of CAP rate (31.6%). The number of phase A1 subtypes remained unmodified across the 3 SCs (SC1, 48; SC2, 48; SC3, 48), whereas both subtypes A2 (SC1, 9; SC2, 14; SC3, 14) and A3 (SC1, 2; SC2, 8; SC3, 10) increased significantly (P<0.028 and P<0.0001, respectively). The A1 subtypes composed more than 90% of all the A phases collected in the descending branches and in the troughs, while the A2 and A3 subtypes were the major representatives (64.3%) of the A phases occurring in the ascending branches. CONCLUSIONS Within the dynamic organization of sleep, the non-random distribution of CAP sequences, with their succession of slow (subtypes A1) and rapid (subtypes A2 and A3) EEG shifts, seem to be responsible for sculpturing EEG synchrony under the driving and alternating forces of NREM and REM sleep.

Multidrug comparison (lorazepam, triazolam, zolpidem, and zopiclone) in situational insomnia: Polysomnographic analysis by means of the cyclic alternating pattern

Since homogeneous samples of insomniacs are difficult to recruit for pharmacotherapy studies, normal sleepers can be used to assess the protective effect of hypnotic drugs, under standardized nonconducive conditions. In particular, a noisy environment is a typical cause of situational insomnia that can be counteracted by a sedative-hypnotic agent. Six healthy middle-aged subjects (three men and three women), with no complaints about sleep, underwent a completely randomized double-blind series of 10 nocturnal polysomnograms with at least 72-h washout intervals. All subjects received a single dose of placebo, zolpidem 10 mg, zopiclone 7.5 mg, lorazepam 1 mg, and triazolam 0.25 mg both under basal and under perturbed conditions. For each individual, five recordings were carried out under basal conditions (sound pressure level not higher than 30 dB) and five recordings under acoustically perturbed conditions (continuous white noise at 55 dB). Sleep quality was assessed by means of a visual analogue scale (VAS). All recordings were scored according to conventional rules (macro-structure) and cyclic alternating pattern (CAP) methodology (microstructure). Statistical analysis was based on a repeated measures analysis-of-variance design integrated by Bonferroni adjusted probabilities. Under placebo, situational insomnia was confirmed by the significant increase in sleep fragmentation (intrasleep wakefulness) and by the significant enhancement of arousal instability (CAP parameters). In contrast to macrostructural information, CAP parameters were highly sensitive in detecting the perturbing effects of noise (mean CAP rate under placebo, 57%) and the protective action of hypnotic drugs during perturbation (mean CAP rate under active medication, 41%). Microstructural analysis enabled us to discriminate hypnotic drugs from placebo, nonbenzodiazepine compounds from benzodiazepine agents, and zopiclone from zolpidem. The latter, in fact, induced the lowest values of CAP rate both under basal (30%) and under noisy (39%) conditions and determined a significant decrease in electroencephalogram arousals. All CAP parameters were significantly correlated with the visual-analogue-scale scores for sleep quality. The use of CAP methodology in a highly standardized model of situational insomnia can be a valid alternative to conventional sleep scoring for the investigation of drug effects on disturbed sleep.