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 PSG 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.Fig. 1FINGER TAPPING MOTOR SEQUENCE TASK (MST) ADMINISTRATION AND RESULTS.: a Participants, randomized to the placebo or eszopiclone visit first, had an introductory/screening visit and two sleep visits, a week apart. Sleep visits involved polysomnography on two consecutive nights (Baseline, MST). Different MST sequences were employed for the two sleep visits and their order was counterbalanced within groups. There is no transfer of learning between MST sequences [83]. Participants trained on the MST before bedtime of the second night and were tested in the morning. Ten minutes after testing, participants trained on a new “control” sequence to evaluate the possibility of eszopiclone “hangover” effects on MST performance. Prior to each MST administration, participants completed the Stanford Sleepiness Scale (SSS) to measure subjective alertness [84]. b The MST requires participants to repeatedly type a five-digit sequence (e.g., 4-1-3-2-4) on a numerically labeled keyboard with the left hand, “as quickly and accurately as possible” for twelve 30 s trials separated by 30 s rest periods. The sequence is displayed at the top of the screen and dots appear beneath it with each keystroke. Participants train before sleep and test on an additional 12 trials after sleep. c Bar graphs of group differences in overnight MST improvement on placebo and eszopiclone with SE bars. Asterisk denotes p < 0.05. d Spindle density at electrode location Cz (inset) on the MST night plotted against overnight MST improvement by group for the placebo and e eszopiclone visits. f Density of spindle-SO events on the MST nights plotted against overnight MST improvement, averaged over the placebo and eszopiclone visits, in the cluster showing a significant correlation (inset). The regression line for the combined groups and visits is shown.Fig. 2ESZOPICLONE EFFECTS ON N2 SLEEP SPINDLE DENSITY.: a Topographical maps of spindle density averaged across nights of the placebo and eszopiclone visits for each group and the comparison of the two visits. Electrodes with a cluster-corrected p < 0.05 are highlighted in green. b Group difference maps (top and middle rows) show significantly greater spindle density in controls than patients on placebo (two significant clusters), but not eszopiclone. Electrodes highlighted in black correspond to p < 0.05. Bottom row: Group by Drug interaction showing electrodes where the eszopiclone effect of increasing spindle density was nonsignificantly greater in patients (p < 0.05). c Top: main effect of Group on spindle density showing a significant cluster. Middle: bar graph of spindle density averaged across the electrodes in the significant cluster with SE bars. Bottom: Drug main effect-eszopiclone increased spindle density at all electrodes.Fig. 3ESZOPICLONE EFFECTS ON N2 SOS AND THEIR COORDINATION WITH SPINDLES.: a Topographical maps of mean SO phase at spindle peak during the placebo and eszopiclone visits (averaged across groups and nights) and a statistical map of their difference. Electrodes highlighted in black meet a threshold of p < 0.05. Circular plots show SO phase at Cz. Lines represent the mean SO phase for each participant and their length represents the consistency of the spindle-SO phase locking. Arrows represent the group means. Right column: mapping of SO phase to topographical maps and circular plots. b Topographical maps of SO and spindle-SO coordination parameters during the placebo and eszopiclone visits and statistical maps of their difference. Electrodes with a cluster-corrected p < 0.05 are highlighted in green. c Plot of the relation of SO amplitude with spindle-SO phase consistency, averaged over the placebo and eszopiclone visits, in the cluster showing a significant correlation (inset shows significant cluster). Regression line is for the combined groups and drug visits.