Relapse Risk after Discontinuation of Risperidone in Alzheimer’s disease

1. Relapse Risk after Discontinuation of Risperidone in Alzheimer’s disease New England Journal of Medicine. 2012 October 18;367:1497-507 Molly Moncrieff Doctor of Pharmacy Candidate University of Georgia College of Pharmacy Class of 2013 Preceptor: Dr. Ali Rahimi

2. Background: Treating Alzheimer’s Disease • Symptoms of psychosis or agitation are common • Associated with signs of distress on the part of the patient, increased burden on caregivers, more rapid cognitive decline, increased likelihood of institutionalization and increased health care costs • Antipsychotic agents show superiority over placebo but have only low to moderate efficacy for the treatment of psychosis and agitation-aggression

3. Purpose • The risk of recurrence of symptoms after discontinuation of antipsychotic medication in patients with Alzheimer’s disease has not been established • Antipsychotic drugs are often discontinued due to concern about adverse effects & federal regulations that urge early discontinuation • Previous trials have had many significant limitations • Why Risperidone? • Studies showed high efficacy and absence of severe side effects at low doses

4. Inclusions/Exclusions • Inclusions: • Outpatients or residents of assisted living facilities or nursing homes • 50 to 95 years of age • Met the criteria for dementia based on the DSM-IV • Met the criteria for probable Alzheimer’s disease based on the National Institute of Neurological and Communicative Disorders and Stoke-Alzheimer’s Disease and Related Disorders Association • Score of 4 or more on the NPI at both screening and baseline on the delusions or hallucinations subscale (psychosis score) or the agitation-aggression subscale (agitation score) • Score of 5 to 26 on the MMSE for the case of outpatient and a score of 2 to 26 in the case of nursing home residents • Exclusions: • History of stroke • History of transient ischemic attack • History of uncontrolled atrial fibrillation

5. Methods • Phase A • Administration of open-label, flexible-dose risperidone for 16 weeks in patients with Alzheimer’s who has psychosis or agitation-aggression • After 16 weeks only patients who had a response to therapy continued to Phase B • Response: reduction of >30% from baseline on the NPI core score & a score of 1 or 2 on the CGI-C scale • Phase B • Patients who responded to risperidone were randomly assigned, in a double blind fashion, into 3 different regimens • Group 1: continuation of risperidone for 32 weeks • Group 2: risperidone for 16 weeks followed by placebo for 16 weeks • Group 3: placebo for 32 weeks • Relapse: increase of >30% from baseline on the NPI core score or a 5 point increase from the score at the end of phase A & a score of 6 or 7 on the CGI-C scale

6. Methods

7. Results • First 16 weeks of Phase B • Placebo group (group 3) compared to the groups that continued to receive risperidone (groups 1 & 2) had an increased risk of relapse [HR=1.94, 95% CI (1.09-3.45), P=0.02] • 24 of 40 patients in group 3 (60%) has a relapse compared to 23 of 70 (33%) of patients in groups 1 & 2 • Second 16 weeks of Phase B • The group that discontinued risperidone at week 16 and switched to placebo (group 2) compared to the group that continued to receive risperidone (group 1) had an increased risk of relapse [HR=4.88, 95% CI (1.08-21.98), P=0.02] • 13 of 27 patients in group 2 (48%) has a relapse compared to 2 of 13 (15%) of patients in group 1

8. Statistics • Kaplan-Meier Curves: • A way of dealing with differing survival time • Time to event • Survival times do not have to be actual survival with death being the event. The event may be any event of interest • Curves that have many small steps usually have a higher number of subjects, whereas curves with large steps usually have a limited number of subjects and are thus not as accurate

9. Conclusion • In Alzheimer’s patients who had psychosis or agitation symptoms decreased while taking risperidone, the time to relapse was shorter among patients who discontinued use of risperidone compared with patients who continued to receive risperidone • Patients with psychosis or agitation-aggression who have a sustained response to antipsychotics for 4 to 8 months have an increased risk of relapse for at least 4 months after discontinuation • This should be weighed against the risk of adverse effects with continuation of treatment • More clinical trials are needed to inform current regulations that govern clinical practice

10. Strengths/Weaknesses • Strengths • Double blinded • Multi-center • Risperidone was the only therapy used • One single pharmacy • Weaknesses: • Inadequate sample size • Adverse events in Phase B • Predictors of relapse after discontinuation • Rating: Ib

11. References • Devanand D.P, et al. Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease. New England Journal of Medicine. 2012 October 18;367:1497-507 • Hyman Bradley T, et al. National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer's & Dementia. 2012 January;8(1):1-13 • Rich Jason T, et al. A practical guide to understanding Kaplan-Meier curves. Otolaryngology- Head and Neck Surgery. 2012 September;143(3):331-336