EFFECTS OF ESZOPICLONE ON SLEEP AND MEMORY IN SCHIZOPHRENIA http://dx.doi.org/10.5665/sleep.2968 The Effects of Eszopiclone on Sleep Spindles and Memory Consolidation in Schizophrenia: A Randomized Placebo-Controlled Trial Erin J. Wamsley, PhD1; Ann K. Shinn, MD, MPH2; Matthew A. Tucker, PhD1; Kim E. Ono, BS3; Sophia K. McKinley, BS1; Alice V. Ely, MS1; Donald C. Goff, MD3; Robert Stickgold, PhD1; Dara S. Manoach, PhD3,4 1Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; 2Psychotic Disorders Division, McLean Hospital, Belmont, MA; 3Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA; 4Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA Study Objectives: In schizophrenia there is a dramatic reduction of sleep spindles that predicts deficient sleep-dependent memory consolidation. Eszopiclone (Lunesta), a non-benzodiazepine hypnotic, acts on γ-aminobutyric acid (GABA) neurons in the thalamic reticular nucleus where spindles are generated. We investigated whether eszopiclone could increase spindles and thereby improve memory consolidation in schizophrenia. Design: In a double-blind design, patients were randomly assigned to receive either placebo or 3 mg of eszopiclone. Patients completed Baseline and Treatment visits, each consisting of two consecutive nights of polysomnography. On the second night of each visit, patients were trained on the motor sequence task (MST) at bedtime and tested the following morning. Setting: Academic research center. Participants: Twenty-one chronic, medicated schizophrenia outpatients. Measurements and Results: We compared the effects of two nights of eszopiclone vs. placebo on stage 2 sleep spindles and overnight changes in MST performance. Eszopiclone increased the number and density of spindles over baseline levels significantly more than placebo, but did not significantly enhance overnight MST improvement. In the combined eszopiclone and placebo groups, spindle number and density predicted overnight MST improvement. Conclusion: Eszopiclone significantly increased sleep spindles, which correlated with overnight motor sequence task improvement. These findings provide partial support for the hypothesis that the spindle deficit in schizophrenia impairs sleep-dependent memory consolidation and may be ameliorated by eszopiclone. Larger samples may be needed to detect a significant effect on memory. Given the general role of sleep spindles in cognition, they offer a promising novel potential target for treating cognitive deficits in schizophrenia. Keywords: Schizophrenia, procedural learning, motor skill, sleep spindles, memory consolidation, automation Citation: Wamsley EJ; Shinn AK; Tucker MA; Ono KE; McKinley SK; Ely AV; Goff DC; Stickgold R; Manoach DS. The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized placebo-controlled trial. SLEEP 2013;36(9):1369-1376. INTRODUCTION sleep8 and impaired memory consolidation,9 yet little is known Cognitive deficits are the strongest predictor of functional about how abnormal sleep contributes to memory consolida- outcome in schizophrenia,1 and antipsychotic drugs (APDs) are tion deficits. Understanding this contribution may open new relatively ineffective in treating them (e.g., Sergi2). Amelio- avenues to treatment. ration of cognitive deficits has thus become a priority of the Recent studies find marked impairments (reduced by 67% schizophrenia research community and is the focus of large- to 100%) of sleep-dependent consolidation of motor proce- scale studies.3 A limitation of these efforts is that cognition is dural memory10-12 and dramatically reduced sleep spindle measured in cross-section. While this provides a valid snapshot activity11-15 in schizophrenia. Sleep spindles are a defining of function, it misses critical aspects of learning and memory characteristic of stage 2 NREM sleep, evident in the EEG as that happen offline, over time and with sleep. Following brief powerful bursts of 12-15 Hz synchronous activity.16 We encoding, memories undergo “consolidation” processes that recently reported that the sleep spindle and memory deficits stabilize, enhance, integrate, and reorganize memory in the are correlated and hypothesized that the reduction in sleep brain. A wealth of evidence from molecular, cellular, neural spindles impairs memory consolidation in schizophrenia.15 network, regional brain activation, and behavioral studies of This hypothesis is consistent with evidence from animal birds,4 rodents,5 cats,6 and humans7 demonstrates that sleep plays studies that sleep spindles are a key mechanism of synaptic a critical role in memory consolidation. This work suggests an plasticity that mediates memory consolidation during sleep17 evolutionarily conserved function for sleep in memory consoli- and from human studies that link spindles to the sleep- dation. In schizophrenia, there is evidence of both abnormal dependent consolidation of both procedural and declarative memory.18 In the present study, we investigated whether eszopiclone (Lunesta), a non-benzodiazepine hypnotic agent Submitted for publication October, 2012 that acts on γ-aminobutyric acid (GABA)ergic neurons in the 19 Submitted in final revised form January, 2013 thalamic reticular nucleus (TRN), where sleep spindles are Accepted for publication February, 2013 generated,20 could increase sleep spindles and thereby improve Address correspondence to: Dara S. Manoach, Psychiatric Neuroimag- memory consolidation in schizophrenia. ing, Massachusetts General Hospital Charlestown Navy Yard, 149 13th While the cause of the spindle deficit in schizophrenia is Street, Room 1.111, Charlestown, MA 02129; Tel: (617) 724-6148; Fax: unknown, reduced spindle activity may reflect TRN dysfunction, (617) 726-4078; E-mail: [email protected] consistent with evidence of TRN abnormalities in schizophrenia.21 SLEEP, Vol. 36, No. 9, 2013 1369 Eszopiclone and Sleep Spindles in Schizophrenia—Wamsley et al The TRN is comprised entirely of GABAergic neurons22 that of schizophrenia, the finger tapping motor sequence task primarily project to glutamatergic thalamic neurons, which then (MST).29,30 Improvement of MST performance occurs after project to the cortex. Cortical neurons, in turn, send glutamatergic sleep—but not after an equivalent period of wake and MST inputs back to N-methyl-D-aspartate acid (NMDA) receptors on improvement—as well as overnight improvement on other TRN neurons. Thus, spindles are mediated by a thalamocor- simple motor skill tasks correlates with the amount of stage tical feedback loop that is regulated by both GABAergic and 2 NREM sleep30 and with the number and density of sleep NMDA-receptor mediated glutamatergic neurotransmission.23 spindles.31-33 In schizophrenia, overnight MST improvement is 24 10,11 Eszopiclone acts on GABAA receptors, particularly on subunits markedly reduced, and in the data from the Baseline visit preferentially expressed in the TRN.19 It has demonstrated safety of the present study reported elsewhere,15 this reduction corre- and sustained efficacy in treating insomnia25 and is approved for lated with spindle number and density, which were also mark- long-term treatment. The potential for eszopiclone to increase edly reduced (by 36% and 38%, respectively). Here we report spindles without causing physiologic tolerance or serious with- the findings from the Treatment visit examining the effects drawal effects,26 and its apparent lack of detrimental effects on of eszopiclone versus placebo on stage 2 sleep spindles and cognition and psychomotor function the following day, make it a overnight MST improvement in patients. viable potential adjunctive agent.27,28 To test the hypothesis that eszopiclone would increase METHODS sleep spindles and thereby improve memory consolidation in schizophrenia, we conducted a double-blind, placebo- Participants controlled study. Medically and clinically stable outpatients Twenty-five schizophrenia outpatients were recruited from an with schizophrenia participated in Baseline and Treatment urban mental health center; 21 completed the study. All had been visits, each consisting of 2 consecutive nights of polysom- maintained on stable doses of second-generation APDs for ≥ 6 nography. We employed the same simple, well-characterized weeks, and 12 took diverse adjunctive medications for anxiety, test of motor procedural memory as in our previous studies agitation, and/or concurrent mood disturbance (see Table S1 in the supplemental material). There were no medication changes during study participation. Potential participants were screened Table 1—Demographic characteristics and description of study samples to exclude those with diagnosed sleep disorders, treatment Placebo Eszopiclone with sleep medications, a history of significant head injury or (n = 11) (n = 10) P neurological illness, and a history of substance abuse or depen- Age (years) 34 ± 9 35 ± 10 0.82 dence within the past 6 months based on patient interview, chart Sex (M/F) 10/1 7/3 0.24 review, and clinician report. Diagnoses were confirmed with 34 Parental Education (years) 15 ± 5 15 ± 5 0.74 Structured Clinical Interviews for DSM-IV and symptoms 35 Length of Illness (years) 10 ± 8 11 ± 9 0.80 were rated with the Positive and Negative Syndrome Scale. PANSS Positive 12 ± 4 13 ± 6 0.69 All participants gave written informed consent. The study was PANSS Negative 13 ± 5 16 ± 6 0.22 approved by the institutional review boards