Antipsychotic Discontinuation in Alzheimer's Disease

Phase 4

Completed

Conditions: Alzheimer Disease
Psychotic Disorders
Agitation
Aggression

Interventions: Drug: risperidone

Registration Number: NCT00417482

Lead Sponsor: New York State Psychiatric Institute

Brief Summary: In patients with Alzheimer's disease (AD) who respond to antipsychotic treatment of psychosis and/or agitation/aggression, the relapse risk after discontinuation is not established. AD patients with psychosis and/or agitation/aggression receive 16 weeks of open risperidone treatment (Phase A). Responders are then randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks, (2) risperidone for 16 weeks followed by placebo for 16 weeks, (3) placebo for 32 weeks. The primary outcome is time to relapse of psychosis/agitation.

Detailed Description: This multicenter study (6 academic sites and 2 non-academic sites) involves treating AD patients (assisted living or nursing home patients, and outpatients) using an atypical antipsychotic, risperidone. In Phase A, 180 AD patients with psychosis and/or agitation/aggression receive open treatment with risperidone for 16 weeks. Responders are randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for the next 32 weeks, (2) risperidone for the next 16 weeks followed by placebo for 16 weeks, or (3) placebo for the next 32 weeks. The primary hypothesis is that in the first 16 weeks of Phase B, relapse risk will be lower with continuation risperidone (Arms 1 + 2) compared to discontinuation on placebo (Arm 3). The secondary hypothesis is that in the second 16 weeks of Phase B, relapse risk will be lower with continuation risperidone (Arm 1) compared to discontinuation on placebo (Arm 2). For both randomized time periods, the proportions who relapse will be compared for interpretive support. This design provides useful data on the efficacy and side effects of longer term treatment with risperidone, and, in particular, critical information about the time to relapse and likelihood of relapse in patients switched from risperidone to placebo. This information is essential to guide the clinician toward optimal use of such medications in one of the most challenging types of patients: the AD patient with psychosis and/or agitation/aggression. The results of this study will also help to address Federal regulations urging early antipsychotic discontinuation in nursing homes.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 180

Inclusion Criteria

Dementia, either sex, age 50-95 years
Probable Alzheimer's disease
Intellectual impairment present for at least 6 months
Mini Mental State Exam (MMSE) score of 5-26 for outpatients and 2-26 for nursing home patients
Availability of informant who has had direct contact with the patient for an average of at least once every week during the 3 months prior to study entry
Meets Neuropsychiatric Inventory (NPI) criteria for either (1) psychosis, or (2) agitation/aggression
Able to mobilize independently (if wheelchair-bound, the patient must be able to self-propel)
Free of psychotropic medication (or able to tolerate washout) for at least 1 week prior to study entry. Low dose antidepressants and sedative/hypnotics allowed if they cannot be washed out and the dose remains stable for the study duration
Expected to complete the study (including all efficacy evaluations) and be without major sensory impairment that would prevent participation in any aspect of the study

Exclusion Criteria

Current primary Axis I psychiatric disorder other than AD
Substance abuse or dependence currently, or within the past year
Dementia due to head trauma
History of allergy to risperidone or intolerance to risperidone
Diffuse Lewy body disease
History of seizure disorder, infectious encephalitis, Parkinson's disease, central nervous system (CNS) neoplasm, tardive dyskinesia, stroke, transient ischemic attack (TIA) or uncontrolled atrial fibrillation
Use of monoamine oxidase inhibitors (MAOIs) and unable to undergo 3-week washout; patients also may not take MAOIs for 2 weeks after completing the study
In treatment with (a) depot antipsychotic within 2 weeks of the screening visit
Untreated or incompletely treated hypothyroidism
Active, unstable medical condition that requires active medication adjustment or surgery
Need for electroconvulsive treatment (ECT)
Significant risk for harm to themselves or others as a result of randomization to placebo
History of malignant neoplasm during the last 5 years

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo-Placebo	risperidone	Placebo for 16 weeks followed by placebo for 16 weeks
Risperidone-risperidone	risperidone	Risperidone for 16 weeks followed by risperidone for 16 weeks
Risperidone-Placebo	risperidone	Risperidone for 16 weeks followed by placebo for 16 weeks

Primary Outcome Measures

Name	Time	Method
Relapse by Study Week 32	0-16 weeks in Phase B (16-32 weeks in study)	A relapse occurred in Phase B (post-randomization) if both of the following criteria were met: 1. Increase in the Neuropsychiatric Inventory (NPI) core score of 30% or more OR a 5-point increase from the baseline NPI score at the end of Phase A 2. A score of 6 (much worse) or 7 (very much worse) on the Clinical Global Impression-Change (CGI-C) at any visit.

Secondary Outcome Measures

Name	Time	Method
Relapse by Study Week 48	16-32 weeks in Phase B (32-48 weeks in study)	Same definition and criteria as the primary outcome
Mini Mental State Exam (MMSE)	Phase B, weeks 1-16 (study weeks 16-32)	The MMSE assesses cognition. Scores range from 0-30, with higher scores indicating better cognition. For each subject, the change in MMSE between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in MMSE over time.
Treatment Emergent Symptoms Scale (TESS)	Phase B, weeks 1-16 (study weeks 16-32)	The Treatment Emergent Symptom Scale (TESS) assesses 26 somatic symptoms. Total scores range from 0-26, with a score of 0 or 1 for each item. Higher scores indicate more somatic symptoms. For each subject, the change in TESS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in TESS over time.
Extrapyramidal Signs (EPS)	Phase B, weeks 1-16 (study weeks 16-32)	Extrapyramidal signs, also known as Parkinsonian signs, refer to signs of tremor, rigidity, and bradykinesia (slowed movement) that are seen in Parkinson's disease. Assessment of extrapyramidal signs (EPS) were made with the use of the Simpson-Angus scale (which ranges from 1-40) with higher scores indicating more extrapyramidal signs. For each subject, the change in EPS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in EPS over time.
AIMS	Phase B, weeks 1-16 (study weeks 16-32)	The Abnormal Involuntary Movement Scale (AIMS) assesses signs of tardive dyskinesia, a movement disorder that can occur with prolonged use of antipsychotic medication. The AIMS score ranges from 0 to 35, with higher scores indicating more severe symptoms. For each subject, the change in AIMS score between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in AIMS over time.
Physical Self-Maintenance Scale (PSMS)	Phase B, weeks 1-16 (study weeks 16-32)	Physical Self-Maintenance Scale, which ranges from 1 to 30, with higher scores indicating WORSE functioning. For each subject, the change in PSMS between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in PSMS (worse functioning) over time.
Weight	Phase B, weeks 1-16 (study weeks 16-32)	For each subject, the change in weight in pounds between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in weight over time.

Trial Locations

Locations (7): WLA VA Medical Center/UCLA, Psychiatry
🇺🇸
Los Angeles, California, United States
University of Iowa College of Medicine
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Iowa City, Iowa, United States
Tuscaloosa VA Medical Center, Department of Psychiatry
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Tuscaloosa, Alabama, United States
New York State Psychiatric Institute, Columbia University
🇺🇸
New York, New York, United States
Mount Sinai School of Medicine, Alzheimer's Disease Research Center
🇺🇸
New York, New York, United States
Research Center for Clinical Studies, Inc.
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Norwalk, Connecticut, United States
Medical University of South Carolina
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North Charleston, South Carolina, United States