The Effects of Eszopiclone on Sleep Spindles and Memory Consolidation in Schizophrenia: A Randomized Placebo-Controlled Trial

Wamsley, Erin J.; Shinn, Ann K.; Tucker, Matthew A.; Ono, Kim E; McKinley, Sophia K.; Ely, Alice V.; Goff, Donald C.; Stickgold, Robert; Manoach, Dara S.

doi:10.5665/sleep.2968

Cited by 109 publications

(84 citation statements)

References 47 publications

(71 reference statements)

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“…In addition, reduced spindle activity in those with schizophrenia was associated with cognitive deficits (Wamsley et al, 2012). Interestingly, the administration of eszopiclone during sleep significantly increased spindle generation in individuals with schizophrenia and the increases correlated with overnight motor sequence task improvement (Wamsley et al, 2013). Taken together, these results suggest that individual differences in the degree to which there is optimal functioning of the TC system may dictate and support normal intellectual abilities (for a review, see Fogel & Smith, 2011).…”

Section: Discussionmentioning

confidence: 73%

Sleep Spindles and Intellectual Ability: Epiphenomenon or Directly Related?

Fang

Sergeeva

Ray

et al. 2017

Journal of Cognitive Neuroscience

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Abstract■ Sleep spindles-short, phasic, oscillatory bursts of activity that characterize non-rapid eye movement sleep-are one of the only electrophysiological oscillations identified as a biological marker of human intelligence (e.g., cognitive abilities commonly assessed using intelligence quotient tests). However, spindles are also important for sleep maintenance and are modulated by circadian factors. Thus, the possibility remains that the relationship between spindles and intelligence quotient may be an epiphenomenon of a putative relationship between good quality sleep and cognitive ability or perhaps modulated by circadian factors such as morningness-eveningness tendencies. We sought to ascertain whether spindles are directly or indirectly related to cognitive abilities using mediation analysis. Here, we show that fast (13.5-16 Hz) parietal but not slow (11-13.5 Hz) frontal spindles in both non-rapid eye movement stage 2 sleep and slow wave sleep are directly related to reasoning abilities (i.e., cognitive abilities that support "fluid intelligence," such as the capacity to identify complex patterns and relationships and the use of logic to solve novel problems) but not verbal abilities (i.e., cognitive abilities that support "crystalized intelligence"; accumulated knowledge and experience) or cognitive abilities that support STM (i.e., the capacity to briefly maintain information in an available state). The relationship between fast spindles and reasoning abilities is independent of the indicators of sleep maintenance and circadian chronotype, thus suggesting that spindles are indeed a biological marker of cognitive abilities and can serve as a window to further explore the physiological and biological substrates that give rise to human intelligence. ■

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Section: Discussionmentioning

confidence: 73%

Sleep Spindles and Intellectual Ability: Epiphenomenon or Directly Related?

Fang

Sergeeva

Ray

et al. 2017

Journal of Cognitive Neuroscience

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“…In a small preliminary study, eszopiclone, which acts on γ-aminobutyric acid (GABA)-ergic neurons in the TRN 73 , significantly increased spindles in schizophrenia but not sleep-dependent memory 30 . In another study that did not include PSG, longerterm administration of eszopiclone improved working memory in schizophrenia, but not symptoms 74 .…”

Section: Discussionmentioning

confidence: 99%

“…To investigate SW-spindle coordination, we analyzed polysomnography (PSG) data from a previously reported study of chronic medicated schizophrenia patients and demographically-matched healthy controls 10,30 . Using this dataset, we previously reported that in the context of normal sleep architecture and quality, patients showed significant reductions in N2 sleep spindle number and density, low sigma (12-13.5Hz) power and cortical spindle coherence.…”

Section: Introductionmentioning

confidence: 99%

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia

Demanuele

Bartsch

Baran

et al. 2016

Sleep

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Demanuele et al., 2016 1 This study is not a clinical trial. Demanuele et al., 2016 3 Coordination of Slow Waves with Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia AbstractStudy Objectives: Schizophrenia patients have correlated deficits in sleep spindle density and sleep-dependent memory consolidation. In addition to spindle density, memory consolidation is thought to rely on the precise temporal coordination of spindles with slow waves (SWs). We investigated whether this coordination is intact in schizophrenia and its relation to motor procedural memory consolidation.Methods: Twenty-one chronic medicated schizophrenia patients and 17 demographicallymatched healthy controls underwent two nights of polysomnography with training on the finger tapping motor sequence task (MST) on the second night and testing the following morning. We detected SWs (0.5-4Hz) and spindles during non-rapid eye-movement (NREM) sleep. We measured SW-spindle phase-amplitude coupling and its relation with overnight improvement of MST performance.Results: Patients did not differ from controls in the timing of SW-spindle coupling. In both groups spindles peaked during the SW upstate. For patients only, the later in the SW upstate that spindles peaked and the more reliable this phase relationship, the greater the overnight MST improvement.Regression models that included both spindle density and SW-spindle coordination predicted overnight improvement significantly better than either parameter alone suggesting that both contribute to memory consolidation.Conclusions: Schizophrenia patients show intact spindle-SW temporal coordination and these timing relationships, together with spindle density, predict sleep-dependent memory consolidation.These relations were seen only in patients suggesting that their memory is more dependent on optimal spindle-SW timing, possibly due to reduced spindle density. Interventions to improve memory may need to both increase spindle density and optimize the coordination of NREM oscillations.

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“…Eszopiclone is known to increase the duration of stage 2 sleep and to act on GABA neurons in the thalamic reticular nucleus where spindles are generated. A small (n ¼ 21) randomized placebo controlled trial noted significantly increased sleep spindle number and density during stage 2 sleep following 2 nights of eszopiclone 3 mg compared to placebo which correlated with enhanced though nonsignificant overnight motor sequence task improvement (Wamsley et al 2013). Previous studies noted that triazolam led to overnight deterioration of motor sequence tasks, although spindles increased, and zolpidem did not differ from placebo in its effects on memory.…”

Section: Place In Therapymentioning

confidence: 99%

Eszopiclone: Review and Clinical Applications in Chronic and Comorbid Insomnia

Najib

2014

Drug Treatment of Sleep Disorders

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Eszopiclone, the active S(+)-enantiomer of zopiclone [(R,S)-zopiclone], was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of insomnia in adult patients !18 years of age, and in 2005 became the first sedative hypnotic approved by the FDA for the long-term treatment of chronic insomnia. It is classified by the FDA as a Schedule IV drug under the Controlled Substances Act and is available in the United States as the brand Lunesta ® in dosages of 1, 2, and 3 mg. Eszopiclone 2 and 3 mg consistently demonstrated significant improvements of the primary variable, latency to persistent sleep, assessed subjectively or objectively, in short-and long-term clinical trials. Additionally, improvements in sleep maintenance, sleep quality, and daytime functioning have also been observed. Eszopiclone 3 mg has been shown to improve insomnia associated with comorbid conditions. Tolerance with eszopiclone was not apparent in any of the sleep parameters for up to 12 months treatment duration and rebound insomnia, where documented, tends to be transient and limited to the first night of withdrawal. Eszopiclone is generally well tolerated and the most frequent adverse event is unpleasant bitter taste. Both eszopiclone and its racemic compound, zopiclone, are nonbenzodiazepine hypnotic agents that are derivatives of the cyclopyrrolone class, with eszopiclone exhibiting greater affinity than the R(À)-enantiomer for the GABA A /benzodiazepine receptor complex; hence the sedative hypnotic effects of the racemate are primarily linked to the S(+)-enantiomer rather than the R(À)-enantiomer. The racemate zopiclone is available as 3.75, 5, and 7.5 mg tablets; the latter contains 3.75 mg of S(+)-zopiclone, which is more than the highest dose (3 mg) available in the United States. Eszopiclone is not marketed in the European Union, as it was too similar to the racemate to be considered a patentable product.

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The Effects of Eszopiclone on Sleep Spindles and Memory Consolidation in Schizophrenia: A Randomized Placebo-Controlled Trial

Cited by 109 publications

References 47 publications

Sleep Spindles and Intellectual Ability: Epiphenomenon or Directly Related?

Sleep Spindles and Intellectual Ability: Epiphenomenon or Directly Related?

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia

Eszopiclone: Review and Clinical Applications in Chronic and Comorbid Insomnia

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