P4‐200: Agmatine prevents scopolamine‐induced impairment in water maze performance

Background: Quetiapine is a novelantipsychotic, approved for the treQuetiapine is a novelantipsychotic, approved for the treatment of schizophrenia and bipolardisorder. Quetiapine is also used off-label for the treatment ofneuropsychiatric symptoms of dementia patients, including sleep disturbance. Studies have shown that quetiapine promotes nighttime sleep recorded bywrist-actigraphy in patients with depression (6). No sleep-promoting drug ornon-pharmacologic intervention has been shown to be highly effective inpatients with dementia. This pilot study was designed to investigate theeffects of quetiapine on sleep disturbance (nighttime awaklenings) in patientswith MCI or dementia. Quetiapine is also used off-label for the treatment of neuropsychiatricsymptoms of dementia patients, including sleep disturbance. Studies have shownthat quetiapine promotes nighttime sleep recorded by wrist-actigraphy inpatients with depression (6). No sleep-promoting drug or non-pharmacologicintervention has been shown to be highly effective in patients with dementia. This pilot study was designed to investigate the effects of quetiapine on sleepdisturbance (nighttime awaklenings) in patients with MCI or dementia. Methods: Study drug was administeredonce daily at bedtime for 1-week placebo run-in (baseline), followed by an6-week quetiapine titration. Quetiapine was started at 25 mg with a fixed doseescalation to 50 mg at week 2. The PI (C. Singer) then followed a flexibleweekly titration in 25 mg increments, to a maximum dose of 200 mg. Placebo andactive drug were administered in identical appearing 25 mg tablets. Subjectstook 5 tablets at bedtime, including a 100 mg tablet and four 25 mg tablets inappropriate placebo-active drug combinations to achieve the scheduled dose. Primary outcomes wereactigraph-scored nighttime sleep and awakenings. Wrist-actigraphs were worn24/7 throughout the trial. Night total sleep time (NTST) was defined as theaverage minutes of sleep in the twelve-hour 20:00 to 08:00 period during eachtreatment condition. Subjective response was assessed by the Sleep DisordersInventory (SDI) and Clinical Global Impression of Change (CGI-C). Results: Fourteen subjects were enrolled. Analyzable data were available for 12 subjects. Wrist-Actigraphy Nighttime sleep (NTST) increased during quetiapine treatment (weeks 1-5) versus placebo baseline. Wake time after sleep onset or WASO wassignificantly reduced at weeks 3 (75 mg; p value 1⁄4 0.030) and 5 (116 mg; pvalue 1⁄4 0.018). Sleep DisordersInventory (SDI) Caregivers andsubjects were blind to treatment and dose. Caregiver rating of sleepdisturbances by SDI significantlyimproved at week 5 (p value 1⁄4 0.004). Mini Mental State Exam (MMSE). General cognition asmeasured by MMSE did not change. Clinical GlobalImpressions Change. No changewas reported in about half of the patients but, at week 5, all patients werejudged to have improved (11% marked improvement (1/9), 44% moderate improvement (4/9), and 22% minimal improvement (2/9)). Note this rating was by the PI whowas not blinded. Tolerability Quetiapine was generally well tolerated with thisconservative dose titration. There was one serious adverse event (SAE) that was “possibly drug related”: (Frequent falls in a subject with a history of falls). There was another SAE, non-drug related, that led to drop out during theplacebo week. Conclusions: Quetiapine appears toincrease nighttime sleep and to reduce the number of nighttime awakenings inpatients with either dementia or MCI. The effect size was very large ascompared to sedative hypnotics trials in young and old insomnia patients. Theimprovement was seen in both objective and subjective measures. The data show atrend towards a dose response curve. These results need to beconfirmed by a larger, randomized trial. Subsequent studies will need toconfirm efficacy and dosing. However, a study with bipolar disorders I and II (21-76 yrs) found a significant effect in depressed patients (300 -800 mg) relative to controls. P4-199 COMBINATION OF NOVEL a7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONISTS WITH EXISTING ALZHEIMER’S TREATMENTS Nick van Goethem, Jos Prickaerts, Maria Gawryl, Dana Hilt, Gerhard K€onig, Maastricht University, Maastricht, Netherlands; EnVivo Pharmaceuticals, Watertown, Massachusetts, United States.