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