Olanzapine in Anxiety Due to Alzheimer's Disease
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Clinical Question: 76yo MWF with vascular dementia presents complaining of persistent anxiety. What medication will be of any help?
Background: Alzheimer's disease is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% patients with dementia. Although new information has emerged on the treatment of psychosis and agitation in dementia, very little is available about the treatment of anxiety symptoms in this population.
Methods
Design - RCT, double-blind, placebo-controlled 6-week study.
Setting-28 sites in US from 12/1996-6/1998.
Patient Population - Eligible patients were >40yo, nursing home residents with score >=3 on any of the Neuropsychiatric Inventory/Nursing Home (NPI/NH) Agitation/Aggression, Delusions, Hallucinations items & MMSE <25. Exclusion criteria: bedridden, h/o Axis I disorder within 12mos prior to study entry, or any other diagnosis of serious neurological condition other than AD that could contribute to psychosis or dementia. No concomitant use of medications with primarily CNS activity (i.e. cholinesterase inhibitors, anticonvulsants, mood stabilizers, other antipsychotics, TCA's, MAOI's, and anticholinergics). Patients were allowed to continue SSRI's, but could not alter the medication after screening. This study used a subset of patients who presented with clinically significant anxiety symptoms, defined as score >=2 on NPI/NH Anxiety item. This patient subgroup of 120 subjects (58.3% of entire study population), was mostly female (72%), evenly divided between those up to 85yo and those older than 85yo, and had mean baseline MMSE 7.43.
Intervention / Control - Olanzapine / Placebo. Benzodiazepines were utilized as rescue medication, up to 4mg/d ativan-equivalents and a total of 21 days during treatment period.
Baseline l-'washout and placebo lead-in period (3-14d)-*randomization via permuted block design to 1 of 4 fixed-dose treatment groups (placebo; olanzapine 5, 10, or 15mg/d)-* Weekly evaluations for up to 6 weeks.
Titration: All patients assigned to olanzapine therapy began at 5mg/d, with subsequent increases of 5mg every 7d for those assigned to 10 and 15mg/d groups.
Blinding-"double-blind," with no specifics
Outcomes- Patients were evaluated at baseline & weekly for up to 6 weeks. NPI/NH = caregiver-rated scales that assess psychopathology in dementia.
- Primary: NPI/NH, including items of Delusions, Hallucinations, Agitation/Aggression and Anxiety, and the Brief Psychiatric Rating Scale for efficacy.
- Secondary: Simpson-Angus Scale, AIMS, and Barnes Akathisia Scale, and MMSE for tolerability and safety. Also included adverse events, vitals signs, weight, lab tests, and ECG's.
Follow-up - 6 week period total. 29 of the anxiety subgroup patients discontinued prior to completion, 11 physician's decision, and 3 d/t noncompliance. Analysis - ITT with LOCF, Mean change from baseline to endpoint was analyzed using ANOVA. Fisher's Exact test was used to analyze categorical data to determine statistical significance.
Validity Randomized and Randomization list concealed? yes Treatment groups similar at baseline? yes. There were no statistically significant differences across treatment groups in baseline characteristics of this subset. (see table 1) Patients starting trial accounted for at conclusion? yes Patients analyzed in groups to which they were randomized? yes Patients and clinicians blinded to treatment? yes Groups treated similarly outside of intervention? yes Do the study population characteristics describe your patient? no-she likely has vascular dementia.
Results For efficacy outcomes - Only patients treated with olanzapine 5mg/d had statistically sig reduction on Anxiety item as compared to placebo (olanz 5: -3.72, placebo: -1.67, p"0.034). This finding also held true in full study group. In overall study, low dose olanzapine (5& 10mg/d) was statistically more effective than placebo at reducing psychosis. When controlling for the improvement in hallucinations from baseline to endpoint, the improvement in anxiety in the olanzapine 5mg/d group remained statistically significant. No statistically sig changes in MMSE scores across treatment groups.
For safety and tolerability outcomes - Somnolence was the only treatment-emergent event that was statistically different in any olanzapine group compared with placebo. When controlling for treatmentemergent somnolence, the improvement in anxiety in the olanzapine 5mg/d group remained statistically significant. Also true when controlled for use of BZ's as rescue medication.
Compliance with Therapies - Not clear how compliance was monitored, but 3 patients were dropped due to "noncompliance."
Adverse Effects - Olanzapine was well tolerated, but 11 patients did withdraw from study d/t adverse event (not specified). Ecchymosis more often in placebo group. Somnolence more often in olanzapine groups. No adverse events, EPS, changes in vital signs, lab values, and ECGs occurred with statistical significance.
Strengths: moderate number of subjects, multicenter
Weaknesses: only anxiety in AD, too many medications on exclusion list, no long-term follow up beyond 6 weeks, no mention what specific adverse events caused patients to drop out How will this study affect your management of the putative patient? not at all-she's already been on olanzapine with no benefit Next steps for further study of this problem: Long term study, broaden subject pool to assess effectiveness in other types of dementia and with other medications used in patients with dementia, improved monitoring/ reporting of AE's.
Presented by Kerry Landry, MD
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