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532. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in patients with Alzheimer’s dementia
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BIOL PSYCHIATRY 2000;47:1S–173S
aldosterone- (AL) concentration. NMDA-antagonists increase SWS (Campbell and Feinberg, 1995). Their action on sleep-endocrine regulation has never been studied in the elderly. We examined the effect of the natural NMDA-antagonist Mg2⫹ in 12 elderly subjects of both gender (range 60 – 80 years) without sleep disturbances. A placebo controlled randomized crossover design with two treatment intervals of 20 days duration separated by 2 weeks washout was used. Mg2⫹ was administered as effervescent tablets in a creeping dose of 10 mM and 20 mM each for 3 days followed by 30 mM for 14 days. At the end of each interval after an accommodation night a sleep EEG was recorded from 23.00 h to 7.00 h. Blood samples were taken every 20 min between 22.00 h and 7.00 h for the analysis of ACTH, C, R and AL. Mg2⫹ led to an increase in SWS (16.5 ⫾ 20.4 min vs. 10.1 ⫾ 15.4 min, p ⬍ 0.05) and delta power. R- (3.7 ⫾ 2.3 M/ml ⫻ min vs. 2.3 ⫾ 1.0 M/ml ⫻ min, p ⬍ 0.05) and AL- (3.6 ⫾ 4.7 M/ml ⫻ min vs. 1.1 ⫾ 0.9 M/ml ⫻ min, p ⬍ 0.05) concentration increased throughout the night, whereas C showed a decrease in the first half of the night around the time of its nadir (8.3 ⫾ 2.4 M/ml ⫻ min vs. 11.8 ⫾ 3.8 M/ml ⫻ min, p ⬍ 0.01). ACTH remained unchanged. Our data suggest that Mg2⫹ can reverse some age-related changes of sleep-endocrine activity, possibly via its NMDA-antagonistic effect.
532. LONG-TERM EFFICACY OF OLANZAPINE IN THE CONTROL OF PSYCHOTIC AND BEHAVIORAL SYMPTOMS IN PATIENTS WITH ALZHEIMER’S DEMENTIA J.S. Street, W.S. Clark, B.E. Juliar, P.D. Feldman, D.L. Kadam, A. Breier Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 A multicenter study was conducted to determine the long-term efficacy and safety of olanzapine in the treatment of psychotic symptoms and behavioral disturbances associated with Alzheimer’s disease. Elderly nursing home patients with dementia (mean age: 83.1 years) and meeting the NINCDS-ADRDA criteria for possible or probable Alzheimer’s disease were enrolled in the study. Following a placebo lead-in period and a 6-week double-blind acute phase, 137 patients who successfully completed the acute phase entered an open-label phase of up to 18 weeks during which they received olanzapine in a dose range of 5, 10, or 15 mg/day. Most patients received 5 mg/day of olanzapine for the majority of the time in the open-label period. The mean change from baseline to endpoint in the sum of the Agitation, Delusions, and Hallucinations items of the Neuropsychiatric Inventory—Nursing Home version was used as the primary efficacy measure (NPI/NH Core Total). Secondary measures included the Total and individual item scores of the NPI/NH, including Occupational Disruptiveness, as well as scores on the BPRS and MMSE. Following treatment with olanzapine, patients’ scores were significantly improved on the Core Total (mean ⫾ SD: ⫺7.55 ⫾ 8.53, p ⬍ .001), Total (⫺17.85 ⫾ 23.72, p ⬍ .001), and 10 of the 13 individual item scores of the NPI/NH, including Occupational Disruptiveness (⫺2.84 ⫾ 3.24, p ⬍ .001). Similarly, olanzapine-treatment resulted in significant improvements in the BPRS Total (⫺6.52 ⫾ 12.76, p ⬍ .001). MMSE scores and the other NPI/NH individual item scores were not significantly changed from baseline. Barnes Akathisia scores were significantly improved from baseline (⫺0.22 ⫾ 0.80, p ⫽ .002), while SimpsonAngus and AIMS scores were not significantly changed. No significant changes occurred in patient ECGs, including QTc interval, nor in any other vital sign or in weight. Treatment-emergent symptoms included somnolence (26% of patients, 94% mild-to-moderate), accidental injury (25% of patients, 91% mild-to-moderate), and rash (22% of patients, 93% mild-to-moderate). In total, these data suggest that olanzapine is an
Saturday Abstracts
effective, generally safe, and well-tolerated long-term treatment for control of psychotic symptoms and behavioral disturbances in elderly patients with Alzheimer’s dementia.
533. OLANZAPINE IN THE PREVENTION OF PSYCHOSIS AMONG NURSING HOME PATIENTS WITH BEHAVIORAL DISTURBANCES ASSOCIATED WITH ALZHEIMER’S DISEASE W.S. Clark, J.S. Street, T.M. Sanger, P.D. Feldman, Alan Breier Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with moderate to severe dementia to determine the efficacy and safety of olanzapine in the treatment of psychotic symptoms and behavioral disturbances associated with Alzheimer’s disease. Subjects met the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association criteria for possible or probable Alzheimer’s disease. Following a placebo lead-in period, 206 patients were randomly assigned to either placebo or a fixed dose of 5, 10, or 15 mg/day of olanzapine for up to 6 weeks of double-blind therapy. The study population consisted of patients who had behavioral disturbances (agitation/aggression) and/or psychosis (hallucinations and/or delusions). Olanzapine provided superior efficacy compared to placebo in reducing psychosis and behavioral disturbances. Additional analyses were conducted to assess the effect of olanzapine relative to placebo in preventing psychosis among patients who did not yet have delusions or hallucinations as measured by the Neuropsychiatric Inventory—Nursing Home version (NPI/NH), a caregiver-rated scale that assesses psychopathology in dementia. Among patients entering the study without either hallucinations or delusions (n ⫽ 76), there was a significantly greater increase in development of these psychotic symptoms among placebo patients compared to olanzapine patients (p ⫽ .006). Similarly, for the larger subset of patients without hallucinations at baseline (n ⫽ 155), a significantly lower proportion of olanzapine patients (7.4%) developed hallucinations compared to placebo patients (21.9%) at endpoint (p ⫽ .045). The proportion of patients developing either hallucinations or delusions during the study was higher among placebo patients compared to each of the three olanzapine treatment groups for each subgroup (patients without delusions, patients without hallucinations, and those without delusions and hallucinations). Olanzapine had a favorable safety profile in each symptom subgroup of patients. Changes in extrapyramidal side effects (Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and the Barnes Akathisia Scale), labs, and vital signs were not clinically significantly different for patients treated with olanzapine compared to placebo.
BIOL PSYCHIATRY 2000;47:1S–173S
aldosterone- (AL) concentration. NMDA-antagonists increase SWS (Campbell and Feinberg, 1995). Their action on sleep-endocrine regulation has never been studied in the elderly. We examined the effect of the natural NMDA-antagonist Mg2⫹ in 12 elderly subjects of both gender (range 60 – 80 years) without sleep disturbances. A placebo controlled randomized crossover design with two treatment intervals of 20 days duration separated by 2 weeks washout was used. Mg2⫹ was administered as effervescent tablets in a creeping dose of 10 mM and 20 mM each for 3 days followed by 30 mM for 14 days. At the end of each interval after an accommodation night a sleep EEG was recorded from 23.00 h to 7.00 h. Blood samples were taken every 20 min between 22.00 h and 7.00 h for the analysis of ACTH, C, R and AL. Mg2⫹ led to an increase in SWS (16.5 ⫾ 20.4 min vs. 10.1 ⫾ 15.4 min, p ⬍ 0.05) and delta power. R- (3.7 ⫾ 2.3 M/ml ⫻ min vs. 2.3 ⫾ 1.0 M/ml ⫻ min, p ⬍ 0.05) and AL- (3.6 ⫾ 4.7 M/ml ⫻ min vs. 1.1 ⫾ 0.9 M/ml ⫻ min, p ⬍ 0.05) concentration increased throughout the night, whereas C showed a decrease in the first half of the night around the time of its nadir (8.3 ⫾ 2.4 M/ml ⫻ min vs. 11.8 ⫾ 3.8 M/ml ⫻ min, p ⬍ 0.01). ACTH remained unchanged. Our data suggest that Mg2⫹ can reverse some age-related changes of sleep-endocrine activity, possibly via its NMDA-antagonistic effect.
532. LONG-TERM EFFICACY OF OLANZAPINE IN THE CONTROL OF PSYCHOTIC AND BEHAVIORAL SYMPTOMS IN PATIENTS WITH ALZHEIMER’S DEMENTIA J.S. Street, W.S. Clark, B.E. Juliar, P.D. Feldman, D.L. Kadam, A. Breier Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 A multicenter study was conducted to determine the long-term efficacy and safety of olanzapine in the treatment of psychotic symptoms and behavioral disturbances associated with Alzheimer’s disease. Elderly nursing home patients with dementia (mean age: 83.1 years) and meeting the NINCDS-ADRDA criteria for possible or probable Alzheimer’s disease were enrolled in the study. Following a placebo lead-in period and a 6-week double-blind acute phase, 137 patients who successfully completed the acute phase entered an open-label phase of up to 18 weeks during which they received olanzapine in a dose range of 5, 10, or 15 mg/day. Most patients received 5 mg/day of olanzapine for the majority of the time in the open-label period. The mean change from baseline to endpoint in the sum of the Agitation, Delusions, and Hallucinations items of the Neuropsychiatric Inventory—Nursing Home version was used as the primary efficacy measure (NPI/NH Core Total). Secondary measures included the Total and individual item scores of the NPI/NH, including Occupational Disruptiveness, as well as scores on the BPRS and MMSE. Following treatment with olanzapine, patients’ scores were significantly improved on the Core Total (mean ⫾ SD: ⫺7.55 ⫾ 8.53, p ⬍ .001), Total (⫺17.85 ⫾ 23.72, p ⬍ .001), and 10 of the 13 individual item scores of the NPI/NH, including Occupational Disruptiveness (⫺2.84 ⫾ 3.24, p ⬍ .001). Similarly, olanzapine-treatment resulted in significant improvements in the BPRS Total (⫺6.52 ⫾ 12.76, p ⬍ .001). MMSE scores and the other NPI/NH individual item scores were not significantly changed from baseline. Barnes Akathisia scores were significantly improved from baseline (⫺0.22 ⫾ 0.80, p ⫽ .002), while SimpsonAngus and AIMS scores were not significantly changed. No significant changes occurred in patient ECGs, including QTc interval, nor in any other vital sign or in weight. Treatment-emergent symptoms included somnolence (26% of patients, 94% mild-to-moderate), accidental injury (25% of patients, 91% mild-to-moderate), and rash (22% of patients, 93% mild-to-moderate). In total, these data suggest that olanzapine is an
Saturday Abstracts
effective, generally safe, and well-tolerated long-term treatment for control of psychotic symptoms and behavioral disturbances in elderly patients with Alzheimer’s dementia.
533. OLANZAPINE IN THE PREVENTION OF PSYCHOSIS AMONG NURSING HOME PATIENTS WITH BEHAVIORAL DISTURBANCES ASSOCIATED WITH ALZHEIMER’S DISEASE W.S. Clark, J.S. Street, T.M. Sanger, P.D. Feldman, Alan Breier Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with moderate to severe dementia to determine the efficacy and safety of olanzapine in the treatment of psychotic symptoms and behavioral disturbances associated with Alzheimer’s disease. Subjects met the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association criteria for possible or probable Alzheimer’s disease. Following a placebo lead-in period, 206 patients were randomly assigned to either placebo or a fixed dose of 5, 10, or 15 mg/day of olanzapine for up to 6 weeks of double-blind therapy. The study population consisted of patients who had behavioral disturbances (agitation/aggression) and/or psychosis (hallucinations and/or delusions). Olanzapine provided superior efficacy compared to placebo in reducing psychosis and behavioral disturbances. Additional analyses were conducted to assess the effect of olanzapine relative to placebo in preventing psychosis among patients who did not yet have delusions or hallucinations as measured by the Neuropsychiatric Inventory—Nursing Home version (NPI/NH), a caregiver-rated scale that assesses psychopathology in dementia. Among patients entering the study without either hallucinations or delusions (n ⫽ 76), there was a significantly greater increase in development of these psychotic symptoms among placebo patients compared to olanzapine patients (p ⫽ .006). Similarly, for the larger subset of patients without hallucinations at baseline (n ⫽ 155), a significantly lower proportion of olanzapine patients (7.4%) developed hallucinations compared to placebo patients (21.9%) at endpoint (p ⫽ .045). The proportion of patients developing either hallucinations or delusions during the study was higher among placebo patients compared to each of the three olanzapine treatment groups for each subgroup (patients without delusions, patients without hallucinations, and those without delusions and hallucinations). Olanzapine had a favorable safety profile in each symptom subgroup of patients. Changes in extrapyramidal side effects (Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and the Barnes Akathisia Scale), labs, and vital signs were not clinically significantly different for patients treated with olanzapine compared to placebo.