Abstract
Sleep spindles, defining oscillations of stage 2 non-rapid eye movement sleep (N2), mediate memory consolidation. Schizophrenia is characterized by reduced spindle activity that correlates with impaired sleep-dependent memory consolidation. In a small, randomized, placebo-controlled pilot study of schizophrenia, eszopiclone (Lunesta®), a nonbenzodiazepine sedative hypnotic, increased N2 spindle density (number/minute) but did not significantly improve memory. This larger double-blind crossover study that included healthy controls investigated whether eszopiclone could both increase N2 spindle density and improve memory. Twenty-six medicated schizophrenia outpatients and 29 healthy controls were randomly assigned to have a placebo or eszopiclone (3 mg) sleep visit first. Each visit involved two consecutive nights of high density polysomnography with training on the Motor Sequence Task (MST) on the second night and testing the following morning. Patients showed a widespread reduction of spindle density and, in both groups, eszopiclone increased spindle density but failed to enhance sleep-dependent procedural memory consolidation. Follow-up analyses revealed that eszopiclone also affected cortical slow oscillations: it decreased their amplitude, increased their duration, and rendered their phase locking with spindles more variable. Regardless of group or visit, the density of coupled spindle-slow oscillation events predicted memory consolidation significantly better than spindle density alone, suggesting that they are a better biomarker of memory consolidation. In conclusion, sleep oscillations are promising targets for improving memory consolidation in schizophrenia, but enhancing spindles is not enough. Effective therapies also need to preserve or enhance cortical slow oscillations and their coordination with thalamic spindles, an interregional dialog that is necessary for sleep-dependent memory consolidation.
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Acknowledgements
We are grateful to the staff of the Massachusetts General Hospital Translational and Clinical Research Center for their support, to our participants, to Carmen Varela and Matthew Wilson for consultation, and to the anonymous reviewers for constructive critiques.
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DSM and RS conceived and designed the trial, and contributed to all aspects of its completion. DM, BB, CD, and RC contributed to conceptualization, methods development, data analysis, and writing. BB, TV, BS, RAF, DC, EP, and CEC contributed to data acquisition, sleep scoring, artifact rejection, and data analysis. AM contributed to task design and programming. DH oversaw all medical aspects of the clinical trial. MV consulted to statistical analysis and study design. All authors reviewed and commented on the finished product.
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Mylonas, D., Baran, B., Demanuele, C. et al. The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized clinical trial. Neuropsychopharmacol. 45, 2189–2197 (2020). https://doi.org/10.1038/s41386-020-00833-2
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DOI: https://doi.org/10.1038/s41386-020-00833-2
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