Schizophrenia
Conditions
Keywords
sleep, memory, schizophrenia, eszopiclone
Brief summary
The investigators will test the hypothesis that the sleep medication, eszopiclone, can normalize brain activity during sleep and improve memory in patients with schizophrenia. The investigators will do this by measuring sleep and memory performance on two conditions separated by one week: taking 3 mg of eszopiclone and taking placebo. The investigators will study healthy subjects and chronic, medicated outpatients with schizophrenia.
Detailed description
Sleep spindles, a defining oscillation of stage 2 non-rapid eye movement sleep (N2), are strongly linked to memory and IQ in healthy individuals. Schizophrenia is characterized by a spindle deficit that correlates with deficient sleep-dependent memory consolidation, symptom severity, IQ and executive function. In a small pilot study of schizophrenia patients, eszopiclone , significantly increased sleep spindles but its effect on memory was not significant. Here, in a larger double-blind, placebo-controlled, cross-over design study, we investigated whether eszopiclone can both increase spindle density and improve memory consolidation. Chronic, medicated schizophrenia outpatients and demographically-matched healthy control participants were randomly assigned to receive either placebo first or 3mg of eszopiclone first for two consecutive nights with high density polysomnography. Placebo and eszopiclone visits were one week apart. Participants were trained on the Motor Sequence Task (MST) at bedtime of the second night of each visit and tested the following morning to probe sleep-dependent motor memory consolidation.
Interventions
DRUGeszopiclone
3 mg of eszopiclone for two consecutive nights (Baseline Night and Experimental Night). Sleep spindle density (primary outcome) is measured for both nights. Memory consolidation (secondary outcome) is measured over Experimental Night.
DRUGplacebo
placebo capsule for two consecutive nights. (Baseline Night and Experimental Night). Sleep spindle density (primary outcome) is measured for both nights. Memory consolidation (secondary outcome) is measured over Experimental Night.
Sponsors
Beth Israel Deaconess Medical Center
Mclean Hospital
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* clinically stable outpatients with schizophrenia, * proficient in English, * able to give informed consent, * maintained on a stable dose of atypical antipsychotic medications for at least 6 weeks prior to enrollment. * healthy Control participants matched as a group to the patients for age, sex, and parental socioeconomic status.
Exclusion criteria
* Substance abuse or dependence within the past six months; * other chronic medical conditions that affect sleep; (- pregnancy/breast feeding; * hepatic impairment; * treatment with inhibitors or inducers of CYP 3A4 or 2E1 enzymes (which metabolize eszopiclone); * a history of head injury resulting in prolonged loss of consciousness or other neurological sequelae; (- mental retardation; (- a diagnosed sleep disorder other than insomnia, * neurological disorder; sleep disorder, other than insomnia, identified in a clinical sleep evaluation. Patients on conventional agents, benzodiazepines, or other sleep agents will be excluded. Potential controls will be excluded for a personal history of mental illness, a family history of schizophrenia spectrum disorder or psychosis, and treatment with medications known to affect sleep or cognition.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sleep Spindle Density | Spindles will be averaged for the Baseline (Night 1) and Experimental Nights (Night 2) | This measure is averaged for Baseline and Experimental nights. Sleep spindle density (number/minute) for non-Rapid Eye Movement Stage 2 sleep (N2) detected at channel Cz based on polysomnographic recordings. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Motor Procedural Memory Performance | Experimental Night (Night 2) | Overnight performance improvement on the finger tapping motor sequence task (MST).The MST involves pressing four numerically labeled keys on a standard keyboard with the fingers of the left hand, repeating a 5 digit sequence as quickly and accurately as possible for 12 trials at 30 seconds each separated by 30 sec rest periods. Different sequences were employed for the Placebo and Drug visits in a counter-balanced order. MST performance is measured as the number of correctly typed sequences in each trial. The primary outcome measure is overnight improvement calculated as the percent increase in average of correct sequences from the last three training trials to the average of first three test trials. Since the outcome measure is calculated as percent improvement from training to test for each participant, there is no highest or lowest possible score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group: Schizophrenia Outpatients with a Structural Clinical Interview confirmed DSM-IV diagnosis of schizophrenia. Participants completed both the Drug and Placebo arms. | 26 |
| Group: Healthy Controls Adult participants screened to exclude a personal history of mental illness, family history of schizophrenia spectrum disorder, and psychoactive medication use. Participants completed both the Drug and Placebo arms. | 29 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Group: Schizophrenia | Group: Healthy Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 29 Participants | 55 Participants |
| Age, Continuous | 32.3 years STANDARD_DEVIATION 7.5 | 30.1 years STANDARD_DEVIATION 6.2 | 31.13 years STANDARD_DEVIATION 6.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 19 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 7 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 14 Participants |
| Race (NIH/OMB) White | 12 Participants | 17 Participants | 29 Participants |
| Region of Enrollment United States | 26 participants | 29 participants | 55 participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 21 Participants | 21 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 31 | 0 / 28 | 0 / 31 |
| other Total, other adverse events | 0 / 28 | 0 / 31 | 0 / 28 | 0 / 31 |
| serious Total, serious adverse events | 0 / 28 | 0 / 31 | 0 / 28 | 0 / 31 |
Outcome results
Primary
Sleep Spindle Density
This measure is averaged for Baseline and Experimental nights. Sleep spindle density (number/minute) for non-Rapid Eye Movement Stage 2 sleep (N2) detected at channel Cz based on polysomnographic recordings.
Time frame: Spindles will be averaged for the Baseline (Night 1) and Experimental Nights (Night 2)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group: Schizophrenia | Sleep Spindle Density | Placebo (placebo capsule) | 2.02 Sleep spindle density (number/minutes) | Standard Deviation 0.44 |
| Group: Schizophrenia | Sleep Spindle Density | Drug (3mg eszopiclone) | 2.25 Sleep spindle density (number/minutes) | Standard Deviation 0.41 |
| Group: Healthy Controls | Sleep Spindle Density | Placebo (placebo capsule) | 2.13 Sleep spindle density (number/minutes) | Standard Deviation 0.51 |
| Group: Healthy Controls | Sleep Spindle Density | Drug (3mg eszopiclone) | 2.44 Sleep spindle density (number/minutes) | Standard Deviation 0.44 |
Secondary
Motor Procedural Memory Performance
Overnight performance improvement on the finger tapping motor sequence task (MST).The MST involves pressing four numerically labeled keys on a standard keyboard with the fingers of the left hand, repeating a 5 digit sequence as quickly and accurately as possible for 12 trials at 30 seconds each separated by 30 sec rest periods. Different sequences were employed for the Placebo and Drug visits in a counter-balanced order. MST performance is measured as the number of correctly typed sequences in each trial. The primary outcome measure is overnight improvement calculated as the percent increase in average of correct sequences from the last three training trials to the average of first three test trials. Since the outcome measure is calculated as percent improvement from training to test for each participant, there is no highest or lowest possible score.
Time frame: Experimental Night (Night 2)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group: Schizophrenia | Motor Procedural Memory Performance | Placebo (Placebo capsule) | 13.35 percentage of improvement on MST perform | Standard Deviation 15.62 |
| Group: Schizophrenia | Motor Procedural Memory Performance | Drug (3mg eszopiclone) | 9.69 percentage of improvement on MST perform | Standard Deviation 17.53 |
| Group: Healthy Controls | Motor Procedural Memory Performance | Placebo (Placebo capsule) | 15.1 percentage of improvement on MST perform | Standard Deviation 12.22 |
| Group: Healthy Controls | Motor Procedural Memory Performance | Drug (3mg eszopiclone) | 16.69 percentage of improvement on MST perform | Standard Deviation 17.14 |