- Email: [email protected]
531. Oral MG2+-supplementation affects sleep-endocrine function in elderly
Saturday Abstracts
father, mother, and siblings did not differ in their family assessment from their counterparts in healthy families. Anorectic restricting patients rated their mother (p ⬍ .05), and the father rated the siblings (p ⬍ .04) as better functioning than healthy families did. Bulimic patients with AN rated themselves as more disturbed than restricting AN patients (p ⬍ .002) or healthy adolescents (p ⬍ .002). Families of bulimic AN patients rated five relationships on the dyadic scale as more dysfunctioning than restricting AN patients: daughter rating father (p ⬍ .007) and mother (p ⬍ .008), father rating daughter (⬍.03), siblings (p.02) and mother rating siblings (⬍.05). The findings suggest specific family-wide patterns of functioning differentiating both types of AN. They confirm a higher degree of dissatisfaction and problematic relationships in AN families than in healthy families.
528. ANTIEMETICS MITIGATE NAUSEA AND VOMITING IN ALZHEIMER’S PATIENTS RECEIVING RIVASTIGMINE N.R. Cutler, R.D. Hartman, J. Messina, R. Anand, J.J. Sramek, S.S. Jhee California Clinical Trials, Beverly Hills, CA 90211; Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936 Cholinesterase inhibitors frequently cause dose-related nausea and vomiting. This prospective, randomized, open-label pilot study was designed to evaluate the efficacy of four pharmacologically distinct antiemetic treatments during a four-week forced dose escalation of rivastigmine from 3 mg/d to 12 mg/d in patients with Alzheimer’s disease. Twenty-six of 82 enrolled patients experienced dose-related nausea and/or vomiting requiring antiemetic treatment. Patients were rated on the Emetic Process Rating Scale (EPRS) every 4h and the Clinical Global Impression (CGI) scale at 72 h. Centrally acting compounds were shown to be effective in preventing nausea and vomiting with rivastigmine, indicating that these effects are centrally mediated.
529. PHARMACOKINETICS OF RIVASTIGMINE AND ITS METABOLITE IN PATIENTS WITH ALZHEIMER’S DISEASE N.R. Cutler, M. Hossain, C. McDonald, F. Pommier, G. Sedek, S.S. Jhee, J.J. Sramek
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hours, a mean T1/2 of 3.6 hours, and a mean Cmax of 11.6 ng/mL. The mean absolute bioavailability of the 6 mg oral dose was 71.7% (range: 21.6 –118.5%) when compared to the 2 mg intravenous infusion normalized for dose. The mean AUC0 –⬀ ratio of NAP 226-90 to rivastigmine was higher with the oral formulation, presumably due to pre-systemic metabolism. The most common adverse event for both formulations was mild to moderate headache (n ⫽ 4, 36%). Thus, the 6 mg oral dose of rivastigmine was safe and well-tolerated, with a high bioavailability.
530. THE INFLUENCE OF AGE ON THE RESPONSE OF MAJOR DEPRESSION TO ELECTROCONVULSIVE THERAPY K. O’Connor (1), R. Knapp (2), T.A. Rummans (1), G.E. Smith (1), M. Husain (4), C. Kellner (2), M. Beale (2), G. Petrides (3), M. Fink (3), A.J. Rush (4), K. Rasmussen (1), K. Snyder (1), H. Bernstein (2), (Core Group, Consortium of Researchers in ECT) Core-Consortium for Research in Electroconvulsive Therapy: (1) Mayo Clinic, Rochester, MN 55905; (2) Medical University of South Carolina, Charleston, SC 29425; (3) Hillside Hospital, Glen Oaks, NY 11004; (4) UT Southwestern Medical Center, Dallas, TX 75235 Major Depression is generally held to be more resistant to treatment in the elderly due to the higher number of lifetime episodes and the greater burden of comorbid illness. Conversely, electroconvulsive therapy (ECT) is one of the most powerful forms of treatment for major depression. In the CORE* Continuation ECT vs Pharmacotherapy Trial, an NIMH funded, multicenter, randomized trial, 246 subjects with primary Major Depressive Disorder (MDD) received an index course of bilateral, moderately suprathreshold ECT. Of these, 210 patients (mean age: 56.9) completed the index course. Patients who by history or mental status testing were considered to have dementia were excluded. Ninety percent [90%] (69/77) of patients in the oldest age group (ⱖ65 years) who completed the index course met strict remitter criteria (HAM-D ⱕ 10 and ⱖ 60% reduction from baseline at two consecutive ratings) compared to 73% percent (44/60) in the youngest group (ⱕ 45 years). Considering all premature exits as non-remitters, a “worst case” analysis, 78% (69/89) of the oldest age group remitted compared to 56% (44/78) for the youngest group (p ⬍ 0.01). In regression analyses, considering age as a continuous variable, age was negatively associated with endpoint HAM-D independently (p ⫽ 0.01) and was marginally associated after adjustment for baseline HAM-D, psychosis status, number of ECT, and number of prior episodes (p ⫽ 0.07). These data do not support the clinical belief that MDD is more resistant to treatment in the elderly at least in the absence of clinically detectable dementia.
California Clinical Trials, Beverly Hills, CA 90211; Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936 Rivastigmine (SDZ ENA 713; Exelon®), (⫹)(S)-N-Ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate, is an acetylcholinesterase inhibitor of the carbamate type approved for the treatment of Alzheimer’s disease. The highest recommended dose of rivastigmine is 6 mg bid; therefore, this open-label, randomized sequence, crossover study was designed to determine the absolute bioavailability of a 6 mg oral dose via comparison with a single 2 mg intravenous dose in patients with probable Alzheimer’s disease who were receiving rivastigmine in a parallel long-term study. A lower intravenous dose was used because a 6 mg intravenous dose could not be given due to tolerability concerns. Serial plasma samples were taken through 12 hours post-dose. The single 6 mg oral dose of rivastigmine was rapidly absorbed, with a mean Tmax of 1.2 hours, a mean T1/2 of 1.7 hours, and a mean Cmax of 25.6 ng/mL. The major metabolite, NAP-226-90, formed by hydrolysis of rivastigmine by cholinesterase, had a mean Tmax of 1.6
531. ORAL MG2ⴙ-SUPPLEMENTATION AFFECTS SLEEP-ENDOCRINE FUNCTION IN ELDERLY K. Held (1), H. Ku¨nzel (1), I.C. Golly (2), A. Steiger (1), H. Murck (1) (1) Max-Planck-Institute of Psychiatry, Department of Psychiatry, Munich, D-80804, Germany; (2) Walther-Straub-Institute of Pharmacology and Toxicology, LMU, Munich, D-80336, Germany During aging slow-wave-sleep (SWS) decreases, accompanied by an increase in cortisol- (C) at its nadir and a decrease in renin- (R) and
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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.
father, mother, and siblings did not differ in their family assessment from their counterparts in healthy families. Anorectic restricting patients rated their mother (p ⬍ .05), and the father rated the siblings (p ⬍ .04) as better functioning than healthy families did. Bulimic patients with AN rated themselves as more disturbed than restricting AN patients (p ⬍ .002) or healthy adolescents (p ⬍ .002). Families of bulimic AN patients rated five relationships on the dyadic scale as more dysfunctioning than restricting AN patients: daughter rating father (p ⬍ .007) and mother (p ⬍ .008), father rating daughter (⬍.03), siblings (p.02) and mother rating siblings (⬍.05). The findings suggest specific family-wide patterns of functioning differentiating both types of AN. They confirm a higher degree of dissatisfaction and problematic relationships in AN families than in healthy families.
528. ANTIEMETICS MITIGATE NAUSEA AND VOMITING IN ALZHEIMER’S PATIENTS RECEIVING RIVASTIGMINE N.R. Cutler, R.D. Hartman, J. Messina, R. Anand, J.J. Sramek, S.S. Jhee California Clinical Trials, Beverly Hills, CA 90211; Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936 Cholinesterase inhibitors frequently cause dose-related nausea and vomiting. This prospective, randomized, open-label pilot study was designed to evaluate the efficacy of four pharmacologically distinct antiemetic treatments during a four-week forced dose escalation of rivastigmine from 3 mg/d to 12 mg/d in patients with Alzheimer’s disease. Twenty-six of 82 enrolled patients experienced dose-related nausea and/or vomiting requiring antiemetic treatment. Patients were rated on the Emetic Process Rating Scale (EPRS) every 4h and the Clinical Global Impression (CGI) scale at 72 h. Centrally acting compounds were shown to be effective in preventing nausea and vomiting with rivastigmine, indicating that these effects are centrally mediated.
529. PHARMACOKINETICS OF RIVASTIGMINE AND ITS METABOLITE IN PATIENTS WITH ALZHEIMER’S DISEASE N.R. Cutler, M. Hossain, C. McDonald, F. Pommier, G. Sedek, S.S. Jhee, J.J. Sramek
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hours, a mean T1/2 of 3.6 hours, and a mean Cmax of 11.6 ng/mL. The mean absolute bioavailability of the 6 mg oral dose was 71.7% (range: 21.6 –118.5%) when compared to the 2 mg intravenous infusion normalized for dose. The mean AUC0 –⬀ ratio of NAP 226-90 to rivastigmine was higher with the oral formulation, presumably due to pre-systemic metabolism. The most common adverse event for both formulations was mild to moderate headache (n ⫽ 4, 36%). Thus, the 6 mg oral dose of rivastigmine was safe and well-tolerated, with a high bioavailability.
530. THE INFLUENCE OF AGE ON THE RESPONSE OF MAJOR DEPRESSION TO ELECTROCONVULSIVE THERAPY K. O’Connor (1), R. Knapp (2), T.A. Rummans (1), G.E. Smith (1), M. Husain (4), C. Kellner (2), M. Beale (2), G. Petrides (3), M. Fink (3), A.J. Rush (4), K. Rasmussen (1), K. Snyder (1), H. Bernstein (2), (Core Group, Consortium of Researchers in ECT) Core-Consortium for Research in Electroconvulsive Therapy: (1) Mayo Clinic, Rochester, MN 55905; (2) Medical University of South Carolina, Charleston, SC 29425; (3) Hillside Hospital, Glen Oaks, NY 11004; (4) UT Southwestern Medical Center, Dallas, TX 75235 Major Depression is generally held to be more resistant to treatment in the elderly due to the higher number of lifetime episodes and the greater burden of comorbid illness. Conversely, electroconvulsive therapy (ECT) is one of the most powerful forms of treatment for major depression. In the CORE* Continuation ECT vs Pharmacotherapy Trial, an NIMH funded, multicenter, randomized trial, 246 subjects with primary Major Depressive Disorder (MDD) received an index course of bilateral, moderately suprathreshold ECT. Of these, 210 patients (mean age: 56.9) completed the index course. Patients who by history or mental status testing were considered to have dementia were excluded. Ninety percent [90%] (69/77) of patients in the oldest age group (ⱖ65 years) who completed the index course met strict remitter criteria (HAM-D ⱕ 10 and ⱖ 60% reduction from baseline at two consecutive ratings) compared to 73% percent (44/60) in the youngest group (ⱕ 45 years). Considering all premature exits as non-remitters, a “worst case” analysis, 78% (69/89) of the oldest age group remitted compared to 56% (44/78) for the youngest group (p ⬍ 0.01). In regression analyses, considering age as a continuous variable, age was negatively associated with endpoint HAM-D independently (p ⫽ 0.01) and was marginally associated after adjustment for baseline HAM-D, psychosis status, number of ECT, and number of prior episodes (p ⫽ 0.07). These data do not support the clinical belief that MDD is more resistant to treatment in the elderly at least in the absence of clinically detectable dementia.
California Clinical Trials, Beverly Hills, CA 90211; Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936 Rivastigmine (SDZ ENA 713; Exelon®), (⫹)(S)-N-Ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate, is an acetylcholinesterase inhibitor of the carbamate type approved for the treatment of Alzheimer’s disease. The highest recommended dose of rivastigmine is 6 mg bid; therefore, this open-label, randomized sequence, crossover study was designed to determine the absolute bioavailability of a 6 mg oral dose via comparison with a single 2 mg intravenous dose in patients with probable Alzheimer’s disease who were receiving rivastigmine in a parallel long-term study. A lower intravenous dose was used because a 6 mg intravenous dose could not be given due to tolerability concerns. Serial plasma samples were taken through 12 hours post-dose. The single 6 mg oral dose of rivastigmine was rapidly absorbed, with a mean Tmax of 1.2 hours, a mean T1/2 of 1.7 hours, and a mean Cmax of 25.6 ng/mL. The major metabolite, NAP-226-90, formed by hydrolysis of rivastigmine by cholinesterase, had a mean Tmax of 1.6
531. ORAL MG2ⴙ-SUPPLEMENTATION AFFECTS SLEEP-ENDOCRINE FUNCTION IN ELDERLY K. Held (1), H. Ku¨nzel (1), I.C. Golly (2), A. Steiger (1), H. Murck (1) (1) Max-Planck-Institute of Psychiatry, Department of Psychiatry, Munich, D-80804, Germany; (2) Walther-Straub-Institute of Pharmacology and Toxicology, LMU, Munich, D-80336, Germany During aging slow-wave-sleep (SWS) decreases, accompanied by an increase in cortisol- (C) at its nadir and a decrease in renin- (R) and
162S
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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.