The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized clinical trial.

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.

Spared and impaired sleep-dependent memory consolidation in schizophrenia.

OBJECTIVE: Cognitive deficits in schizophrenia are the strongest predictor of disability and effective treatment is lacking. This reflects our limited mechanistic understanding and consequent lack of treatment targets. In schizophrenia, impaired sleep-dependent memory consolidation correlates with reduced sleep spindle activity, suggesting sleep spindles as a potentially treatable mechanism. In the present study we investigated whether sleep-dependent memory consolidation deficits in schizophrenia are selective. METHODS: Schizophrenia patients and healthy individuals performed three tasks that have been shown to undergo sleep-dependent consolidation: the Word Pair Task (verbal declarative memory), the Visual Discrimination Task (visuoperceptual procedural memory), and the Tone Task (statistical learning). Memory consolidation was tested 24 h later, after a night of sleep. RESULTS: Compared with controls, schizophrenia patients showed reduced overnight consolidation of word pair learning. In contrast, both groups showed similar significant overnight consolidation of visuoperceptual procedural memory. Neither group showed overnight consolidation of statistical learning. CONCLUSION: The present findings extend the known deficits in sleep-dependent memory consolidation in schizophrenia to verbal declarative memory, a core, disabling cognitive deficit. In contrast, visuoperceptual procedural memory was spared. These findings support the hypothesis that sleep-dependent memory consolidation deficits in schizophrenia are selective, possibly limited to tasks that rely on spindles. These findings reinforce the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of schizophrenia and suggest sleep physiology as a potentially treatable mechanism.

Prospective memory in schizophrenia: relationship to medication management skills, neurocognition, and symptoms in individuals with schizophrenia.

OBJECTIVE: Impaired adherence to medication regimens is a serious concern for individuals with schizophrenia linked to relapse and poorer outcomes. One possible reason for poor adherence to medication is poor ability to remember future intentions, labeled prospective memory skills. It has been demonstrated in several studies that individuals with schizophrenia have impairments in prospective memory that are linked to everyday life skills. However, there have been no studies, to our knowledge, examining the relationship of a clinical measure of prospective memory to medication management skills, a key element of successful adherence. METHODS: In this Study 41 individuals with schizophrenia and 25 healthy adults were administered a standardized test battery that included measures of prospective memory, medication management skills, neurocognition, and symptoms. RESULTS: Individuals with schizophrenia demonstrated impairments in prospective memory (both time and event-based) relative to healthy controls. Performance on the test of prospective memory was correlated with the standardized measure of medication management in individuals with schizophrenia. Moreover, the test of prospective memory predicted skills in medication adherence even after measures of neurocognition were accounted for. CONCLUSIONS: This suggests that prospective memory may play a key role in medication management skills and thus should be a target of cognitive remediation programs.