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
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
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
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
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
Methods
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
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
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
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
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